Cardiovascular Safety of Atomoxetine and Methylphenidate in Patients With Attention-Deficit/Hyperactivity Disorder in Japan: A Self-Controlled Case Series Study

Abstract

Objective:

To investigate the association between atomoxetine or methylphenidate use and arrhythmia, heart failure (HF), stroke, and myocardial infarction (MI) in attention-deficit/hyperactivity disorder (ADHD) patients mainly focused on the people of working age.

Methods:

In a self-controlled case series study using a Japanese claims database, we identified events of arrhythmia, HF, stroke, and MI among 15,472 atomoxetine new users and 12,059 methylphenidate new users. Adjusted incidence rate ratios (aIRRs) of outcome events were estimated using multivariable conditional Poisson regression.

Results:

An increased risk of arrhythmia was observed during the first 7 days after the initial atomoxetine exposure (aIRR 6.22, 95% CI [1.90, 20.35]) and in the subsequent exposure (3.23, [1.58, 6.64]). No association was found between methylphenidate exposure and arrhythmia, nor between atomoxetine or methylphenidate exposure and HF. The limited number of stroke and MI cases prevented thorough analysis.

Conclusions:

Clinicians should consider monitoring for arrhythmia after patients initiating or re-initiating atomoxetine.

Keywords

ADHD Atomoxetine Methylphenidate Cardiovascular events Selfcontrolled case series study

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common lifelong neurodevelopmental disorders beginning in childhood and continuing into adulthood. The prevalence of ADHD worldwide was estimated at 7.2% in children and adolescents and 6.8% in adults (Song et al., 2021; Thomas et al., 2015). Clinical guidelines recommend the use of pharmacological treatments to manage ADHD symptoms, although approved and recommended medications vary across regions and countries (Coghill et al., 2023; Wolraich et al., 2019). In Asia, methylphenidate (MPH) is the most commonly used medication for ADHD (Jeong et al., 2021; Shin et al., 2016). In Japan, in addition to MPH the stimulant, atomoxetine (ATX) the non-stimulant is widely used to treat ADHD (Kikuchi et al., 2021; Okumura et al., 2019; M. Yoshida et al., 2020).

Although ADHD medications are generally well tolerated, there is an ongoing debate about their potential cardiovascular (CV) adverse events. Both ATX and MPH can increase heart rate and blood pressure by affecting the noradrenergic and dopaminergic transmission pathways (Liang et al., 2018). The regulatory authorities in the United States, European Union, and Japan require warnings and precautions of serious CV events in the package inserts of ATX and MPH (FDA/CDER, 2002; MHRA/EMA, 2014; PMDA, 2020). Clinical guidelines also recommend cardiac monitoring before and after initiating treatment (Coghill et al., 2023; NICE, 2018; Wolraich et al., 2019).

Several observational studies and meta-analyses have attempted to examine the association between ADHD medications and CV events, but the findings have been inconsistent. These studies differ in the type of medications, severity and type of CV events, patient age, and methodology (Cooper et al., 2011; Habel et al., 2011; Hennissen et al., 2017; Liu et al., 2019; Shin et al., 2016; Zhang et al., 2022). Previous studies have mainly focused on serious CV events such as sudden death, myocardial infarction (MI), and stroke, and the study populations were mainly children and adolescents (Cooper et al., 2011; Hennissen et al., 2017; Schelleman et al., 2011; Shin et al., 2016). The investigation of non-fatal CV events of clinical meaningfulness such as arrhythmia and heart failure (HF) is also of importance while pending evidence. Risk assessment for adults is needed given the persistence of ADHD symptoms and long-term use of medication. Most previous studies using databases from the US and Europe have focused on the Caucasian population (Cooper et al., 2011; Habel et al., 2011; Liu et al., 2019; Schelleman et al., 2011). The limited studies in the Asian population have only reported the CV risk of MPH, and the risk of ATX in the Asian population should be further explored (Jeong et al., 2021; Shin et al., 2016).

To address these issues, we conducted a population-based self-controlled case series (SCCS) study in Japan to assess the association between exposure to ATX or MPH and non-fatal CV events, including arrhythmia, HF, stroke, and MI. To our knowledge, this is the first case-only study to investigate the association between ATX exposure and CV risk.

Methods

Data Source

We conducted a population-based study using claims data from the JMDC database (JMDC Inc., Tokyo, Japan), from 01 January 2005 to 31 December 2020. The JMDC database has accumulated claims data since 2005 from health insurance societies for company employees and their dependent family members aged <75 years (Nagai et al., 2021). As of December 2020, the database contains data for approximately 12 million enrollees, representing around 9.5% of the total population in Japan.

The anonymized JMDC datasets include information such as sex, year, and month of birth, outpatient and inpatient diagnoses, drugs prescribed, and procedures provided. These diagnoses, prescriptions, and procedures are coded using the International Classification of Diseases, Tenth Revision (ICD-10) codes, the Anatomical Therapeutic Chemical (ATC) codes together with the Japan-specific YJ (Yakka Joho) codes (code according to the National Health Insurance Drug List), and the Japanese procedure codes. The advantage of the JMDC database is its ability to track an individual’s medical information across different healthcare facilities under the same health insurance, making it widely used for epidemiology studies in Japan (Fukasawa et al., 2023; Masuda et al., 2023; S. Yoshida et al., 2022).

The study was approved by the Ethics Committee of Kyoto University Graduate School and the Faculty of Medicine (No. R3166-1). Informed consent from patients was not required as only anonymized data was used. The study follows the reporting guideline and checklist for the reporting of studies conducted using observational routinely collected health data—statement for pharmacoepidemiology (RECORD-PE) (Langan et al., 2018).

Self-Controlled Case Series Study Design

We adopted an SCCS design in the study (Iwagami et al., 2021; Petersen et al., 2016). We selected patients who experienced both a CV event and exposure to ADHD medication and compared the risk of CV events bi-directionally during the observation period with and without the exposure. The SCCS design assesses whether triggering effects exists during the exposure, while a cohort study assesses whether there are more cumulative effects in the exposed patients than in those who were not exposed (Jackson, 2016; Shin et al., 2016). The SCCS design has a major strength in that it minimizes confounding by implicitly controlling both measured and unmeasured time-invariant confounding factors, as each case acts as its own control (Iwagami et al., 2021; Petersen et al., 2016; Shin et al., 2016).

The design was deemed appropriate for investigating the causality between ADHD medications and the CV events based on the following assumptions: 1) the occurrence of non-fatal CV events is rare and does not affect the observation period, 2) the focus was on the first occurrence of CV events if a case experienced multiple events during the observation period to avoid the potential bias that a prior event may influence the probability of subsequent events, and 3) the occurrence of CV events is not expected to impact subsequent exposure to ATX or MPH, given the limited pharmacological treatment options for ADHD (Chen et al., 2020; Jeong et al., 2021; Man et al., 2020; Shin et al., 2016).

Patients

Cases were identified as ADHD patients who received at least one prescription of ATX or MPH, and experienced an incident CV event of arrhythmia, HF, stroke, or MI with a recorded diagnosis during the study observation period (from 01 April 2012 to 31 December 2020), and had at least one claim with a diagnosis of ADHD within 180 days prior to their first prescription. We did not set age restrictions for the patients receiving ADHD medications. Previous validation studies for diagnoses from claims data in Japan found the following positive predictive values (PPV) for CV events: 1.000 (0.787–1.000) for HF, 1.000 (0.786–1.000) for ischemic stroke, and 0.825 (0.765–0.875) for acute MI when defined by a combination of ICD-10 codes and drug information or procedure codes (Ando et al., 2018; Fujihara et al., 2021; Ono et al., 2020). Thus, we defined incident CV events as the first recorded diagnoses of arrhythmia, HF, stroke, or MI, in conjunction with specific drug prescriptions or procedures (Supplemental Table S3). The index date was defined as the date of the first prescription of ATX or MPH. Cases were included as new users if there was no prescription for ATX or MPH within at least 180 days prior to their first ADHD prescription.

The observation period was set beginning from 01 April 2012, because claims records in the national health insurance reimbursement scheme in Japan lack information on dates before 31 March 2012 (Fukasawa et al., 2021). The follow-up continued until the end of database enrolment or 31 December 2020, unless censored due to death, or switching from ATX or MPH to another ADHD treatment or combination. We excluded patients with a history of CV events prior to the observation period. We also excluded patients whose index date was the same as their CV event diagnosis, since without specific timing-level information the causal association cannot be decided.

Exposures

The exposure risk periods were divided into 1 to 7 days, 8 to 14 days, 15 to 28 days, 29 to 56 days, and >56 days after the initial exposure and the whole subsequent exposure period (Figure 1) (Jeong et al., 2021; Shin et al., 2016). A grace period of 14 days was defined, during which the exposure risk period was considered uninterrupted if the gap between the end date of the prescription and the start date of the next prescription was within 14 days (Raman et al., 2013). On the other hand, a subsequent exposure period is counted if the gap is over 14 days. ADHD patients sometimes take drug holidays depending on their life schedules and clinical conditions. So, the subsequent exposure period is classified separately from the initial exposure period. To minimize the impact of the occurrence of an event on subsequent exposures, two consecutive pre-exposure periods were defined as 1 to 30 days and 31 to 60 days before the index date to evaluate whether a recent CV event affects the likelihood of the ATX or MPH prescription (Petersen et al., 2016; Shin et al., 2016). All the remaining time was defined as unexposed baseline periods.

Figure 1.

Illustration of self-controlled case series design. The self-controlled case series study design and timeline for an individual with an incident cardiovascular event (arrhythmia, heart failure, stroke, or myocardial infarction). Such an incident event can happen at any time during the observation period.

Statistical Analysis

We calculated the baseline characteristics using count and proportion for categorical variables, and mean and standard deviation for continuous variables. To evaluate the association between exposure to ATX or MPH and the CV risk of arrhythmia or HF in ADHD patients in Japan, we used a multivariable conditional Poisson regression model to calculate adjusted incidence rate ratios (aIRRs) and their corresponding 95% confidence intervals (CIs) in the pre-exposure and exposure risk periods compared to unexposed baseline periods. The time-varying covariates were adjusted for the outcomes of arrhythmia and HF respectively. In the model for arrhythmia, we included time-varying covariates of age and comedications of antidepressants, antipsychotics, antiepileptics, anti-infective medications (macrolides, fluoroquinolones, triazole, and tetrazole derivatives), bronchodilators, and systemic catecholamines (Supplemental Table S1). For HF, we included the time-varying covariates of age and comedications of neurological medications, non-steroidal anti-inflammatory drugs (NSAIDs), antidiabetic medications, and antihypertensives (Habel et al., 2011; Page et al., 2016; Schelleman et al., 2011; Tadrous et al., 2021; Tisdale et al., 2020; Winterstein et al., 2012). Due to the limited number of cases identified, we could not analyze the outcomes of stroke and MI (Table 1). We also conducted a subgroup analysis in adults aged ≥18 years.

Table 1.

Characteristics of ADHD Patients With Atomoxetine/Methylphenidate Treatment and CV Events.

	Atomoxetine				Methylphenidate
	Arrhythmia (N = 142)	Heart failure (N = 25)	Stroke (N = 8)	MI (N = 0)	Arrhythmia (N = 69)	Heart failure (N = 12)	Stroke (N = 13)	MI (N = 1)
Duration (years)
Total observation period, mean (SD)	5.5 (2.5)	6.4 (2.7)	7.0 (2.5)	0	5.3 (2.5)	4.5 (3.2)	5.5 (2.8)	1.0
Pre-exposure observation period, mean (SD)	2.9 (2.1)	3.5 (2.4)	2.9 (2.4)	0	3.2 (1.9)	3.4 (2.3)	3.2 (2.0)	0.8
Exposure period, mean (SD)	0.9 (1.4)	0.7 (1.2)	1.2 (1.8)	0	0.8 (0.9)	0.3 (0.5)	1.3 (1.8)	0.1
Post-exposure observation period, mean (SD)	2.0 (2.0)	2.6 (2.5)	3.1 (2.3)	0	1.7 (1.8)	0.9 (1.3)	1.5 (1.3)	0.1
No. of CV events
Exposed period	29	5	1	0	12	0	2	0
Unexposed period	113	20	7	0	57	12	11	1
Demographics
Female, n (%)	63 (44.4)	10 (40.0)	4 (50.0)	0	27 (39.1)	4 (33.3)	5 (38.5)	0
Age at first exposure (years), mean (SD)	35.2 (13.2)	33.5 (17.8)	42.2 (19.2)	0	33.7 (14.2)	31.4 (19.2)	47.4 (10.6)	55.3
Age category at first exposure, n (%)
Less than 18 years	15 (10.6)	7 (28.0)	2 (25.0)	0	12 (17.4)	4 (33.3)	0	0
18 to 40 years	70 (49.3)	9 (36.0)	0	0	31 (44.9)	4 (33.3)	4 (30.8)	0
41 to 64 years	52 (38.7)	9 (36.0)	5 (62.5)	0	25 (36.2)	4 (33.3)	8 (61.5)	1 (100)
65 years and older	2 (1.4)	0	1 (12.5)	0	1 (1.5%)	0	1 (7.7)	0
Age at first event (years), mean (SD)	35.7 (13.2)	34.0 (18.9)	43.7 (21.5)	0	34.1 (13.9)	31.1 (19.4)	48.3 (9.2)	57.8
Comorbidities, n (%)
Depressive episode	106 (74.7)	14 (56.0)	5 (62.5)	0	54 (78.3)	7 (58.3)	12 (92.3)	1 (100)
Psychotic disorders	63 (44.4)	6 (24.0)	4 (50.0)	0	31 (45.0)	3 (25.0)	6 (46.2)	0
Manic episode	11 (7.8)	0	3 (37.5)	0	3 (4.4)	1 (8.3)	2 (15.4)	0
Bipolar affective disorder	60 (42.3)	7 (28.0)	4 (50.0)	0	17 (24.6)	4 (33.3)	7 (53.9)	0
Autism spectrum disorder	25 (17.6)	6 (24.0)	0	0	20 (29.0)	6 (50.0)	1 (7.7)	1 (100)
Narcolepsy	5 (3.5)	0	0	0	1 (1.5)	0	0	0
Obesity	11 (7.8)	2 (8.0)	3 (37.5)	0	5 (7.3)	4 (33.3)	2 (15.4)	0
Diabetes	37 (26.1)	8 (32.0)	4 (50.0)	0	19 (27.5)	7 (58.3)	7 (53.9)	1 (100)
Hypertension	53 (37.3)	11 (44.0)	5 (62.5)	0	30 (43.5)	5 (41.7)	9 (69.2)	1 (100)
Hyperlipidemia	59 (41.6)	13 (52.0)	5 (62.5)	0	28 (40.6)	5 (41.7)	10 (76.9)	1 (100)
Cancer	8 (5.6)	4 (16.0)	0	0	3 (4.4)	2 (16.7)	1 (7.7)	1 (100)
Comedications, n (%)
Atomoxetine	NA	NA	NA	NA	21 (30.4)	7 (58.3)	4 (30.8)	1 (100)
Methylphenidate	26 (18.3)	5 (20.0)	0	0	NA	NA	NA	NA
Antidepressants	101 (71.1)	12 (48.0)	5 (62.5)	0	47 (68.1)	5 (41.7)	9 (69.2)	0
Antipsychotics	90 (63.4)	14 (56.0)	5 (62.5)	0	51 (73.9)	8 (66.7)	11 (84.6)	0
Antiepileptics	47 (33.1)	8 (32.0)	5 (62.5)	0	19 (27.5)	3 (25.0)	6 (46.2)	1 (100)
Anti-infective medications	110 (77.5)	19 (76.0)	8 (100)	0	59 (85.5)	10 (83.3)	5 (38.5)	0
Bronchodilators	61 (43.0)	14 (56.0)	4 (50.0)	0	34 (49.3)	6 (50.0)	6 (46.2)	0
Systemic catecholamines	38 (26.8)	16 (64.0)	3 (37.5)	0	19 (27.5)	8 (66.7)	12 (92.3)	1 (100)
Neurological medications	105 (73.9)	15 (60.0)	6 (75.0)	0	46 (66.7)	6 (50.0)	12 (92.3)	1 (100)
NSAIDs	130 (91.6)	24 (96.0)	8 (100)	0	60 (87.0)	10 (83.3)	13 (100)	1 (100)
Antidiabetic medications	7 (4.9)	4 (16.0)	2 (25.0)	0	4 (5.8)	1 (8.3)	2 (15.4)	0
Antihypertensives	40 (28.2)	8 (32.0)	7 (87.5)	0	21 (30.4)	9 (75.0)	7 (53.9)	1 (100)

Note. Comorbidities are defined as at least one record or diagnosis during the pre-specified observation period. Comedications are defined as medication use prescribed during the pre-specified observation period. The pre-exposure observation period is defined as the observation period prior to the start of the drug exposure period. The post-exposure observation period is defined as the observation period after the end of the drug exposure period. ADHD = attention-deficit/hyperactivity disorder; CV = cardiovascular; MI = myocardial infarction; NA = not available; NSAIDs = non-steroidal anti-inflammatory drugs; SD = standard deviation.

Sensitivity analyses were performed by shortening the grace period to 7 days, limiting the pre-exposure period to 1 to 30 days before the index date, and not censoring the observation at the switch or add-on of alternative ADHD treatment. The use of ATX or MPH was adjusted in the sensitivity analysis in which the switch or add-on of alternative ADHD treatment was not censored. The SAS statistical software version 9.4 (SAS Institute Inc, NC, USA) was used for data manipulation and analysis of baseline characteristics. The R software version 4.2.1 (R Foundation for Statistical Computing, IN, USA) including the SCCS package was used for the SCCS analysis.

Results

Study Population and Characteristics

In total, we identified 15,472 ATX new users and 12,059 MPH new users with ADHD diagnoses. In the ATX group, 142 had an incident event of arrhythmia, 25 had HF, 8 had a stroke, and no patients had MI (Figure 2a). In the MPH group, 69 had an incident event of arrhythmia, 12 had HF, 13 had a stroke, and 1 patient had a MI (Figure 2b).

Figure 2.

Flowchart of data collection in the study: (a) shows the ATX user group, and (b) shows the MPH user group.

In the ATX group, the mean total observation periods were 5.5 to 7.0 years, with exposure periods of 0.7 to 1.2 years, pre-exposure observation periods of 2.9 to 3.5 years, and post-exposure observation periods of 2.0 to 3.1 years. In the MPH group, the mean total observation periods were 4.5 to 5.5 years, with exposure periods of 0.3 to 1.3 years, pre-exposure observation periods of 3.2 to 3.4 years, and post-exposure observation periods of 0.9 to 1.7 years.

In the ATX group, the mean ages at first exposure were 33.5 to 42.2 years and 10.6 to 28.0% were less than 18 years old, with the mean ages at the first event of 34.0 to 43.7 years, 40.0 to 50.0% were females (Table 1). In the MPH group, the mean ages at first exposure were 31.4 to 47.4 years and 17.4 to 33.3% were less than 18 years old, with the mean ages at the first event of 31.1 to 48.3 years, 33.3 to 39.1% were females. The most common comorbidities were depressive episodes (ATX group, 56.0–74.7%; MPH group, 58.3–92.3%), hypertension (ATX group, 37.3–62.5%; MPH group, 41.7–69.2%), and hyperlipidemia (ATX group, 41.6–62.5%; MPH group, 40.6–76.9%). The most prescribed medications were antidepressants (ATX group, 48.0–71.1%; MPH group, 41.7–69.2%), antipsychotics (ATX group, 56.0–63.4%; MPH group, 66.7–84.6%), anti-infective medications (ATX group, 76.0–100%; MPH group, 38.5–85.5%), neurological medication (ATX group, 60.0–75.0%; MPH group, 50.0–92.3%), and NSAIDs (ATX group, 91.6–100%; MPH group, 83.3–100%).

Primary Analysis

In the ATX user group, an increased risk of arrhythmia was observed during the first 7 days after the initial exposure (aIRR 6.22, 95% CI [1.90, 20.35]) and in the subsequent exposure (3.23, [1.58, 6.64]) (Table 2). No increased risk of arrhythmia was observed in the MPH group. No increase in HF risk was observed in either group, except for an aIRR increase in the MPH pre-exposure period 31 to 60 days prior to initiation.

Table 2.

Self-Controlled Case Series Analyses for the Association Between ADHD Medication Treatment and First CV Event.

	Adjusted IRR [95% CI]
	Atomoxetine		Methylphenidate
	Arrhythmia	Heart failure	Arrhythmia	Heart failure
Primary analysis	(N = 142)	(N = 25)	(N = 69)	(N = 12)
Baseline	Reference (1.00)	Reference (1.00)	Reference (1.00)	Reference (1.00)
Pre-exposure
31–60 days	2.40 [0.86, 6.71]	NA	2.26 [0.52, 9.89]	224.39 [13.91, 3,620.50]
1–30 days	0.57 [0.08, 4.18]	NA	NA	NA
Initial exposure
1–7 days	6.22 [1.90, 20.35]	NA	NA	NA
8–14 days	2.15 [0.29, 15.77]	NA	4.19 [0.53, 33.07]	NA
15–28 days	NA	NA	2.78 [0.36, 21.65]	NA
29–56 days	NA	NA	2.32 [0.29, 18.43]	NA
>56 days	1.09 [0.45, 2.61]	10.25 [0.89, 117.66]	1.11 [0.24, 5.01]	NA
Subsequent exposure	3.23 [1.58, 6.64]	3.28 [0.50, 21.58]	1.37 [0.43, 4.35]	NA
Subgroup analysis (Adult, ≥18 years old)	(N = 127)	(N = 18)	(N = 57)	(N = 8)
Baseline	Reference (1.00)	Reference (1.00)	Reference (1.00)	Reference (1.00)
Pre-exposure
31–60 days	2.58 [0.91, 7.26]	NA	2.66 [0.62, 11.47]	NA
1–30 days	0.64 [0.09, 4.66]	NA	NA	NA
Initial exposure
1–7 days	6.79 [2.07, 22.28]	NA	NA	NA
8–14 days	NA	NA	3.78 [0.50, 28.39]	NA
15–28 days	NA	NA	2.70 [0.36, 20.16]	NA
29–56 days	NA	NA	1.69 [0.21, 13.70]	NA
>56 days	1.13 [0.46, 2.76]	8.17 [0.58, 115.28]	0.71 [0.12, 4.07]	NA
Subsequent exposure	2.90 [1.31, 6.45]	2.24 [0.14, 36.51]	1.19 [0.36, 3.89]	NA
Sensitivity analysis
Grace period (7 days)
Baseline	Reference (1.00)	Reference (1.00)	Reference (1.00)	Reference (1.00)
Pre-exposure
31–60 days	2.33 [0.83, 6.52]	NA	2.47 [0.59, 10.35]	1,936.14 [112.17, 33,420.49]
1–30 days	0.57 [0.08, 4.17]	NA	NA	NA
Initial exposure
1–7 days	6.04 [1.84, 19.87]	NA	NA	NA
8–14 days	2.33 [0.32, 17.07]	NA	4.93 [0.67, 36.41]	NA
15–28 days	NA	NA	4.29 [0.58, 31.95]	NA
29–56 days	NA	NA	3.03 [0.40, 22.71]	NA
>56 days	0.63 [0.17, 2.32]	4.39 [0.33, 58.90]	1.87 [0.46, 7.63]	NA
Subsequent exposure	2.59 [1.27, 5.28]	1.55 [0.16, 14.57]	1.34 [0.47, 3.86]	NA
Pre-exposure period (30 days)
Baseline	Reference (1.00)	Reference (1.00)	Reference (1.00)	Reference (1.00)
Pre-exposure
1–30 days	0.54 [0.07, 3.94]	NA	NA	NA
Initial exposure
1–7 days	5.88 [1.80, 19.21]	NA	NA	NA
8–14 days	2.04 [0.28, 14.99]	NA	3.93 [0.50, 30.95]	NA
15–28 days	NA	NA	2.60 [0.33, 20.28]	NA
29–56 days	NA	NA	2.18 [0.27, 17.33]	NA
>56 days	1.03 [0.43, 2.48]	10.58 [0.92, 121.99]	1.04 [0.23, 4.72]	NA
Subsequent exposure	3.10 [1.52, 6.36]	3.41 [0.52, 22.41]	1.31 [0.41, 4.15]	NA
No censoring at switch to or addition of alternative ADHD treatment exposure
Baseline	Reference (1.00)	Reference (1.00)	Reference (1.00)	Reference (1.00)
Pre-exposure
31–60 days	2.08 [0.75, 5.80]	NA	1.94 [0.45, 8.29]	15.99 [1.36, 187.64]
1–30 days	0.49 [0.07, 3.54]	NA	NA	NA
Initial exposure
1–7 days	5.17 [1.59, 16.80]	NA	NA	NA
8–14 days	1.79 [0.25, 13.09]	NA	3.33 [0.44, 25.34]	NA
15–28 days	NA	NA	1.57 [0.19, 12.74]	NA
29–56 days	NA	NA	1.24 [0.15, 9.99]	NA
>56 days	1.11 [0.49, 2.48]	13.04 [1.30, 130.87]	0.39 [0.09, 1.70]	NA
Subsequent exposure	2.14 [1.09, 4.22]	6.42 [1.27, 32.48]	1.05 [0.41, 2.69]	NA

Note. IRR of arrhythmia was adjusted for time-varying age and comedications of alternative ADHD medication, antidepressants, antipsychotics, antiepileptics, anti-infective medications, bronchodilators, and systemic catecholamines. IRR of heart failure was adjusted for time-varying age and comedications of alternative ADHD medication, neurological medications, NSAIDs, antidiabetic medications, and antihypertensives. ADHD = attention-deficit/hyperactivity disorder; CI = confidence interval; CV = cardiovascular; IRR = incidence rate ratio; NA = not available; NSAIDs = non-steroidal anti-inflammatory drugs.

Subgroup Analysis in the Adult Population

The subgroup analysis in the adult population (≥18 years old) showed consistently the trend of increased arrhythmia risk in the ATX group in the first 7 days after initial ATX exposure (6.79, [2.07, 22.28]) and in the subsequent exposure (2.90, [1.31, 6.45]) (Table 2). No increased risk of arrhythmia was observed in the MPH users. HF risk was not observed in either the ATX users or the MPH users. The association between HF risk and the MPH pre-exposure period was not found in the subgroup analysis.

Sensitivity Analysis

The increased risk of arrhythmia during the first 7 days after initial ATX exposure and subsequent exposure remained robust in all sensitivity analyses, regardless of adjusting the length of the pre-exposure period, grace period, or without censoring follow-up when the alternative ADHD medication exposure was switched or added on (Table 2). No increased risk of arrhythmia was observed in the MPH users. A risk increase in HF in ATX users was observed more than 56 days after initial exposure and in the subsequent exposure when follow-up was not censored for switch or add-on to MPH. Increased HF risk in the pre-exposure period 31 to 60 days prior to MPH initiation was also observed in the sensitivity analyses.

Discussion

Major Findings

In this population-based SCCS study of patients with ADHD, we found that 7 days after the initiation of ATX and re-initiation were associated with the risk of arrhythmia. However, we found no association between MPH use and arrhythmia, nor between ATX or MPH use and HF. The findings were robust across subgroup analysis in adults and sensitivity analyses. The limited number of stroke and MI cases precluded a detailed analysis.

Interpretation of Our Findings

ATX use is associated with a small but significant increase in systolic and diastolic blood pressure, as well as heart rate in ADHD patients (Liang et al., 2018). The biological actions of ATX on blood pressure and heart rate plausibly explain the increased risk of arrhythmia observed in the study (Liang et al., 2018). Two cohort studies in the US compared serious CV risks including serious cardiac arrhythmia or ventricular arrhythmia in prevalent or new users versus non-users and did not find evidence of increased serious CV risks in children and adolescents using ADHD medications including ATX (Houghton et al., 2020; Schelleman et al., 2011). However, the authors noted that a relative increase in arrhythmia should not be ruled out due to the low number of events. A most recent meta-analysis suggested no significant association between ADHD medications and the risk of CV diseases across age groups, but also mentioned that a modest risk increase, especially for tachyarrhythmias should not be ruled out (Zhang et al., 2022). An SCCS study in Korea found an increased risk of arrhythmia associated with MPH use among children and young people (Shin et al., 2016). We did not find a risk increase in arrhythmia associated with MPH use in Japan. In our study, we focused on arrhythmia events requiring medical or surgical interventions and the target population has a broader age range in which children and adolescents were 17.4% of the total population. These might explain the difference in results, while future research would be warranted to assess this in detail.

Although regulatory authorities put warnings and precautions of serious CV events in package inserts and clinical guidelines highlight the importance of cardiac monitoring (Coghill et al., 2023; FDA/CDER, 2002; MHRA/EMA, 2014; NICE, 2018; PMDA, 2020; Wolraich et al., 2019), a recent study using the same JMDC database revealed that Japanese physicians may not have been well aware and implemented cardiac testing before and after initiating ATX (Imagawa et al., 2018). Since we defined CV events based on the ICD-10 code diagnosis in combination with drug prescriptions or procedures, the increased CV risk observed after ATX exposure is of clinical meaningfulness in the real world. Thus, although the absolute risk is considered low, the finding of an increased risk of arrhythmia after initiation and re-initiation of ATX reminds physicians of the importance of cardiac monitoring when prescribing ATX (Zhang et al., 2022).

The risk of HF was observed highest in the pre-exposure period 31 to 60 days before the MPH initiation but not in the pre-exposure 1 to 30 days before MPH initiation nor during the exposure periods. Considering that HF is a precaution but not a contraindication for ADHD patients in the Japanese label for MPH, this result indicates that physicians may choose to prescribe MPH to patients experiencing HF in real-world clinical practice with careful consideration after their symptoms become stable (PMDA, 2020). A similar observation for MI events was confirmed in an SCCS study conducted in Korea, in which risk increase was observed the highest during the MPH pre-exposure period (Jeong et al., 2021). It was considered that MPH does not trigger the CV event and can still be safely used for patients with prior history of such CV event after careful clinical consideration (Jeong et al., 2021). The increased risk of HF was not observed during ADHD drug exposure, except for in the sensitivity analysis of ATX users more than 56 days after the initial exposure when follow-up was not censored at the switch or add-on to MPH. This may implicate a potential synergistic effect of ATX and MPH on the CV system (Liang et al., 2018). Nevertheless, further research is needed due to the small sample size resulting from a rare incidence rate and the limited information on dose strength (Zhang et al., 2022).

Strengths of the Study

Our study has several strengths. First, our analysis was based on patient data from one of the largest claims databases available for commercial use in Japan, allowing us to track CV events across various medical facilities. Second, we defined CV events by combining ICD-10 codes with information on drug prescriptions, procedures, or hospitalization, resulting in higher PPV and more clinical meaningfulness. Previous studies have primarily used ICD-9/10 codes to assess CV events, but in Japan, validation studies have shown that solely relying on ICD-10 codes has a low PPV, around 10% in HF cases (Fujihara et al., 2021). Combining the ICD-10 codes with additional information on prescriptions or procedures significantly improved the validity of the diagnosis (Fujihara et al., 2021). Third, we employed the SCCS design, which implicitly adjusts for both measured and unmeasured time-invariant confounders, reducing the likelihood of bias from unmeasured confounders, a common challenge in observational studies.

Limitations of the Study

Our study also has several limitations. First, the JMDC database has limited data on patients over 65 years of age, and there is no data on patients over 75 years old, as all insurance participants are company employees and their families (Nagai et al., 2021). As the use of ADHD medications is lifelong and the CV risk may vary in different age groups, our study results should be viewed with caution. The limited number of events in children did not allow us to perform a subgroup analysis in the children population. However, we performed a subgroup analysis in adults mainly focused on the people of working age, and the results were observed similar with those of the main analysis. Besides, further research on the older adult population is necessary. Second, the results from the Japanese population may not be generalizable to other ethnic groups or countries since risks of CV diseases vary across ethnic groups and the choices of ADHD medications differ across countries (NICE, 2018; Okumura et al., 2019; Turana et al., 2021; Wolraich et al., 2019). Third, the SCCS design cannot implicitly adjust for time-varying confounders, which may influence the results over the relatively long observation period (Iwagami et al., 2021; Petersen et al., 2016). However, we adjusted key time-varying covariates of comedications to minimize potential bias. We did not include mental disorder comorbidities in the adjustment of time-varying covariates, considering that algorithms based on administrative codes would not provide acceptable validity for identifying mental disorders (Townsend et al., 2012). Therefore, our results may be biased by mental health status. Fourth, the claims database cannot provide information on drug adherence, which may lead to misclassification of exposure length and affect the results (Nagai et al., 2021). However, adherence to ADHD medications is believed to be high and we accounted for it in both main and sensitivity analyses by defining grace periods for the remaining drugs. Last, the number of strokes and MIs was small, which prevented us from performing further analysis. This may reflect the rare occurrence of strokes or MIs in Japanese ADHD patients in real-world settings (Zhang et al., 2022).

Conclusions

The use of ATX in ADHD patients in Japan is associated with a risk increase in arrhythmia, specifically during the first 7 days after the initial and subsequent exposure. Clinicians should consider careful cardiac monitoring after patients initiating or re-initiating the use of ATX.

Supplemental Material

sj-docx-1-jad-10.1177_10870547231214993 – Supplemental material for Cardiovascular Safety of Atomoxetine and Methylphenidate in Patients With Attention-Deficit/Hyperactivity Disorder in Japan: A Self-Controlled Case Series Study

Supplemental material, sj-docx-1-jad-10.1177_10870547231214993 for Cardiovascular Safety of Atomoxetine and Methylphenidate in Patients With Attention-Deficit/Hyperactivity Disorder in Japan: A Self-Controlled Case Series Study by Yunlong Zheng, Toshiki Fukasawa, Fumitaka Yamaguchi, Masato Takeuchi and Koji Kawakami in Journal of Attention Disorders

Footnotes

Acknowledgements

The authors thank Dr. Guy Harris of Dmed () for his support with the writing of the manuscript.

Author Contributions

Y.Z. and T.F. formulated the study concept and design and performed the statistical analysis. Y.Z. wrote the manuscript. F.Y. provided critical comments from the viewpoint of a cardiologist. All authors contributed to the discussion, and reviewed and approved the final manuscript for submission.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Y.Z. is an employee of Takeda Pharmaceutical Company Limited; however, Takeda Pharmaceutical Company Limited was not involved in this study. T.F. has been employed by the Department of Digital Health and Epidemiology, an Industry-Academia Collaboration Course supported by Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Real World Data Co., Ltd., and Mitsubishi Corporation; and has received consulting fees from Real World Data Co., Ltd. and speaker fees from Asahi Kasei Pharma Corporation and EPS Corporation. F.Y. declares no conflict of interest. M.T. received consulting fees from Eisai Co., Ltd. K.K. received research grants from Eisai Co., Ltd., Kyowa Kirin Co., Ltd., OMRON Corporation, and Toppan Inc.; consulting fees from Advanced Medical Care Inc., JMDC Inc., and Shin Nippon Biomedical Laboratories Ltd.; executive compensation from Cancer Intelligence Care Systems, Inc.; honoraria from Chugai Pharmaceutical Co., Ltd., and Pharma Business Academy.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethics Approval

The study was approved by the Ethics Committee of Kyoto University Graduate School and the Faculty of Medicine (No. R3166-1).

Consent to Participate

Informed consent from patients was not required as only anonymized data was used.

Consent for Publication

Patient privacy and confidentiality were preserved since all individual identifiers were removed at the database creation.

ORCID iDs

Yunlong Zheng

Toshiki Fukasawa

Koji Kawakami

Availability of Data and Material

The data that support the findings of this study are available from the JMDC claims database provided by JMDC Inc. However, the data are not publicly available due to the privacy policy of JMDC Inc.

Supplemental Material

Supplemental material for this article is available online.

Author Biographies

Yunlong Zheng, MS, MBA, is a PhD-course student in the Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University. His research interests include ADHD and other psychiatric and neurologic disorders.

Toshiki Fukasawa, MS, is an assistant professor in the Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University. His research interests include clinical epidemiology and pharmacoepidemiology in all clinical areas.

Fumitaka Yamaguchi, MD, is a PhD-course student in the Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University. His research interests include cardiology and internal medicine.

Masato Takeuchi, MD, PhD, is an associate professor in the Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University. His research interests include clinical epidemiology and pharmacoepidemiology in all clinical areas.

Koji Kawakami, MD, PhD, is the professor in the Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University. His research interests include clinical epidemiology and pharmacoepidemiology in all clinical areas.

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