Treatment Patterns and Healthcare Resource Utilization Among Patients with Obstructive Hypertrophic Cardiomyopathy in Japan: A Claims Database Study

Hypertrophic cardiomyopathy (HCM) is a chronic and often progressive myocardial disorder defined by left ventricular (LV) hypertrophy that cannot be explained by another cardiac, systemic, or metabolic disease [1‐3]. Most patients with HCM have normal life expectancy without the need for major treatments; however, patients remain at risk of significant cardiovascular adverse events (heart failure [HF], malignant ventricular arrhythmias, atrial fibrillation [AF], and stroke). HCM has two subtypes: obstructive HCM and nonobstructive HCM based on the presence and absence of LV outflow tract (LVOT) obstruction. Obstructive HCM and nonobstructive HCM are defined as the presence and absence of LVOT obstruction at peak LVOT outflow gradient ≥ 30 mmHg at rest or provocation, respectively [2, 3]. Obstructive HCM is associated with an increased risk of disease progression and long-term cardiac complications with increased mortality [4, 5].

The current Japanese treatment guidelines claim that treatment recommendation is based on small, nonrandomized, uncontrolled studies; the availability of limited evidence has resulted in a “by consensus” recommendation based on empirical use [2]. The Japanese Circulation Society (JCS)/Japanese Heart Failure Society (JHFS) guidelines recommend beta-blockers (BBs), non-dihydropyridine (DHP) calcium channel blockers (CCBs), and sodium channel blockers (SCBs) at the same level as first-line pharmacological treatment for obstructive HCM [2]. In contrast, both European and U.S. guidelines position SCBs as a second-line option, to be considered only after BBs or CCBs have proven insufficient [1, 3]. BBs and CCBs have negative inotropic and negative chronotropic effects, which are expected to improve symptoms and reduce the LV pressure gradient [2]. BBs are effective in obstructive HCM where the sympathetic nerve is activated due to obstruction, resulting in hypercontraction; BBs act by reducing the pressure gradient during exertion more than that at rest, whereas CCBs reduce the pressure gradient both at rest and during exertion and improve diastolic dysfunction. SCBs have negative inotropic effects and reduce the LV pressure gradient and relieve cardiac symptoms [2].

According to the guideline, caution is advised regarding adverse events with these drugs, and careful dose adjustment may be necessary. BBs are recommended to be used at the maximum dose and are well tolerated; however, attention must be paid to adverse events such as hypotension and bradycardia. It is recommended to initiate BBs at a low dose and increase to a target dose with due consideration for the efficacy and adverse events. Similarly, the dose of CCBs should be increased to a maximum tolerated dose while monitoring for adverse events, blood pressure, and heart rate [2]. SCBs are also associated with adverse events such as anticholinergic effects (e.g., constipation, dry eyes/mouth, dysuria), hypoglycemia, and QT prolongation. Consequently, performing an electrocardiogram before starting SCBs and monitoring blood levels are important considerations for management [2].

Few studies have explored the use of current treatment for obstructive HCM in Japan and other countries. A cross-sectional database study undertaken by Terasaka et al. indicated that 64% (N = 2450) of patients received BBs, 25.4% received non-DHP CCBs, and 29.5% received SCBs [6]. In a study conducted by Enzan et al., 56.8% (N = 3553) of patients with HCM received BBs, 49.6% received angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs), 26.9% received loop diuretics, 15.6% received mineralocorticoid receptor antagonists (MCRAs), and 4.2% received thiazides [7]. The Kochi RYOMA study reported that 41% (N = 293) of patients received BBs; 27% received CCBs, ACEis, or ARBs, and anticoagulation therapy; 22% received antiarrhythmic drugs; and 17% received diuretics [8, 9]. Mavacamten, recently approved in Japan on March 27, 2025, for HCM treatment, is a first-in-class cardiac myosin ATPase inhibitor that reduces contractility and improves symptoms by limiting actin–myosin crossbridge formation [10, 11].

Currently, no data are available on the treatment sequence for patients with obstructive HCM in real-world clinical practice in Japan. As HCM is a life-long disease, understanding the current treatment pattern and identifying its issues will help improve HCM management. Therefore, we conducted this retrospective longitudinal study to evaluate the treatment pattern and time to treatment changes, including discontinuation, switching, add-on, and dose reduction/increase, in patients with obstructive HCM. The study also assessed the incidence of nonpharmacological treatments and healthcare resource utilization (HCRU) associated with the diagnosis and treatment of obstructive HCM. To specifically observe treatment patterns initiated for HCM, we excluded patients who were prescribed BBs, CCBs, or SCBs before HCM diagnosis. This approach was chosen to avoid confounding from treatment changes made for other comorbidities.

This is the first study to describe the treatment patterns from the initial treatment of obstructive HCM in Japan. In the present study, the most common index medication was BB only (74.19%), followed by BB + SCB (10.42%), SCB (8.93%), BB + CCB (1.99%), CCB (3.72%), BB + CCB + SCB (0.5%), and CCB + SCB (0.25%).

In a database study conducted by Owens et al. in the U.S., 52.5% of patients with symptomatic obstructive HCM were treated with BB only, 17.7% with BB and CCB, 11.7% with CCB, and 2.4% with disopyramide [14]. A total of 15.7% of patients with obstructive HCM received nonpharmacological treatment [14]. A recent study conducted by Butzner et al. in the USA reported that 65.8% of patients with symptomatic obstructive HCM were treated with BB only, 11.9% with BB and CCB, 21.1% with CCB, and 1.2% with disopyramide [15]. Similarly, a German study conducted by Sedaghat-Hamedani et al. reported that among patients receiving all types of treatment, 46% were receiving first-line treatment with BB monotherapy, 23% were receiving CCB monotherapy, 9% were treated with a combination of BBs and CCBs, fewer than 1% were receiving a combination of BBs or a combination of CCBs, and 22% were not receiving any treatment for obstructive HCM [16]. Real-world data from England and Spain also showed that BBs were the most common initial treatment, followed by CCBs [17, 18]. In our study, 20.1% of patients were prescribed SCB as initial treatment, which is quite unique compared with that reported in the U.S. and German studies [15, 16]. The most probable explanation would be that cibenzoline is not available in the U.S. and Europe; however, in Japan, it is a widely used treatment for obstructive HCM [19]. Another possible reason for the high prescription rate of SCBs observed in our study is that SCBs are listed with the same level of evidence as BBs and CCBs in the JCS guidelines for the treatment of obstructive HCM [2]. As mentioned earlier, current Japanese treatment guidelines claim that treatment recommendation is based on small, nonrandomized, uncontrolled studies; the availability of limited evidence has resulted in a “by consensus” recommendation based on empirical use [2]. The mean ± SD age of patients included in this study was 75.5 ± 11.7 years, which was older compared with the age reported in the U.S. (58 ± 14 years), Italian (70 ± 14 years), and German (60 years) studies [14, 16, 20]. In addition, patients in the present study had more comorbidities; the frequency of hypertension was 88.6%, which was higher compared with 69.4% in the U.S. study [14]. In the present study, the number of patients who had received any change to their treatment during the first 12 months was 30.5%, which was lower compared with that reported in the U.S. study (43.8%) [14]. Notably, treatment discontinuation rates were lower in Japan (16.6%) than in the U.S. (35.9%) [14]. The lower rates of discontinuation reported in Japan could be attributed to the following reasons: (1) unlike U.S. database studies that often focus on symptomatic patients, our study did not distinguish between symptomatic and asymptomatic individuals, potentially reflecting different treatment urgencies; (2) very few patients transitioned to nonpharmacological treatment in Japan; and (3) the predominantly elderly population with comorbidities in our study may have demonstrated higher adherence to follow-up visits. An additional factor would be the careful dose adjustment by Japanese physicians, especially during the first 1–3 months to manage potential adverse events. Another important finding from our study was that the discontinuation rate of SCBs at 12 months was the highest (22.2%) compared with that in the BB (16%) and CCB (12%) groups. Moreover, the reduction in dose was the highest in the SCB group (22.2%) compared with that in the BB (12%) and CCB (4%) groups. This might reflect the difficulties in the management of adverse events with SCBs, including anticholinergic effects, QT prolongation, and hypoglycemia [2, 21]. The Japanese guidelines recommend the use of SCBs while also advising caution in prescribing due to potential side effects [2]. In this study, we also investigated the dose distribution during the first 3 months after initial treatment with bisoprolol, carvedilol, verapamil, diltiazem, cibenzoline, and disopyramide. These drugs are the mainstay of treatment for HCM in Japan [2]. The data from this study demonstrated that these drugs are prescribed at low doses at treatment initiation and are carefully increased over 3 months. In all treatment groups, it was demonstrated that the majority of patients were prescribed the lowest dose possible. Although the JCS/JHFS guidelines recommend that BBs and CCBs can be used up to the maximum tolerated dose, our findings suggest a conservative approach in routine clinical practice [2]. A supplemental cross-sectional study (January 1, 2021, to December 31, 2021) was conducted in patients with obstructive HCM to confirm our results in a larger patient population. The results from this study were consistent with the findings from our study (data not shown). Compared with the prescription during the first 3 months, doses of bisoprolol and carvedilol increased; however, doses of cibenzoline remained low. Overall, the majority of patients were prescribed low doses compared with the maximum dose advocated in the prescribing information. The observed pattern of low-dose prescribing in HCM likely reflects a combination of physician caution and patient intolerance to therapy. Guidelines such as JCS/JHFS 2018 and international recommendations advocate individualized titration of BBs and CCBs to balance benefits with risks such as bradycardia, hypotension, and atrioventricular block [1‐3]. BBs are generally well tolerated but should be initiated at low doses and adjusted based on heart rate, blood pressure, and symptoms [2, 3]. Verapamil and diltiazem also require careful titration due to the risks of worsening LVOT obstruction and pulmonary edema, particularly in patients with high gradients or pulmonary hypertension [1, 2]. The 2024 American Heart Association (AHA)/American College of Cardiology (ACC) guidelines recommend assessing BB efficacy by physiological response (e.g., heart rate suppression), rather than fixed dosing thresholds [3]. The European Society of Cardiology guidelines similarly recommend titration to the maximally tolerated dose while acknowledging that patients with small LV volumes or comorbidities may not tolerate higher doses, particularly of vasodilators [1]. A majority of the patients in this study were prescribed doses of SCBs lower than the minimum dose recommended in the prescribing information [22‐24]. Emerging evidence indicates that agents such as disopyramide may retain efficacy at lower doses, potentially minimizing side effects, even though this may suggest undertreatment [25]. Even with the recently approved drug mavacamten, a careful dose adjustment based on LV ejection fraction (LVEF) is advised, with therapy interruption or down-titration necessary if LVEF falls below 50% [3]. The appropriate dosage for HCM remains unknown because each standard-of-care drug does not have an indication for HCM.

This study provides key insights into the treatment patterns for patients with obstructive HCM in a real-world clinical setting in Japan. Patients with obstructive HCM in Japan had a high SCB prescription rate and low rates of treatment discontinuation and treatment changes. The study demonstrated the treatment pattern of obstructive HCM under the current limited treatment options that would require careful dose adjustment to avoid adverse events. Further analysis is needed to clarify the treatment selection criteria and rationale by physicians or patients.