Outcome of alcohol septal ablation in mildly symptomatic patients with hypertrophic obstructive cardiomyopathy: A comparison with medical therapy

Abstract Objective The aim of this study was primarily to determine efficacy after alcohol septal ablation (ASA) in mildly symptomatic patients (NYHA class II) with hypertrophic obstructive cardiomyopathy (HOCM), as compared to medical therapy. Methods This retrospective study included 163 mildly symptomatic patients with HOCM evaluated in Beijing Anzhen Hospital between March 2001 and August 2019, consisting of the medical group (n = 105) and the ASA group (n = 58). All‐cause mortality and HCM‐related death were mainly observed. Results Follow‐up was completed in 161 patients and the median follow‐up was 6.0 years. Compared to medically treated patients, patients post‐ASA had comparable survival free of all‐cause mortality (98.3% and 95.1% vs. 93.0% and 83.1% at 5 and 10 years, respectively; p = 0.374). Survival free of HCM‐related death was also similar between ASA and medical groups (98.3% and 95.1% vs. 94.3% and 86.2% at 5 and 10 years, respectively; p = 0.608). However, compared to medical therapy, ASA had advantages on the improvement of NYHA class (1.4 ± 0.6 vs. 2.1 ± 0.5, p = .000) and lower occurrence of new‐onset atrial fibrillation (AF) (7.8% vs. 20.4%, p = .048). Multivariate analysis demonstrated that resting LVOT gradient at the last clinical check‐up was an independent predictor of all‐cause mortality (HR = 1.021, 95%CI 1.002–1.040, p = .027). Conclusion This registry suggests that mildly symptomatic patients with HOCM treated with ASA have comparable survival to that of medically treated patients, with the improvement of NYHA class and lower occurrence of new‐onset AF. All‐cause mortality is independently associated with resting LVOT gradient at the last clinical check‐up.

tion. 2 Comorbidities of participants included hypertension, coronary artery disease, diabetes, chronic kidney disease and stroke. Medical group included mildly symptomatic patients who obtained sufficient symptom relief after medication (e.g., β-blockers and verapamil).
Mildly symptomatic patients met the inclusion criteria for ASA, including: (1) Intolerant to optimal medical therapy; (2) Had a strong wish for symptomatic relief; (3) LVOT gradient≥50 mmHg at rest or after provocation. Consecutive patients with the following criteria were excluded: (1) The refusal of patients; (2) Presence of severe comorbidities; (3) Presence of need for concomitant surgical procedure (e.g., coronary artery bypass grafting); (4) Septal thickness ≥ 30 mm or in the absence of appropriate coronary anatomy; (5) Presence of complete left bundle branch block; (6) The high risk of SCD, such as: family history of premature SCD, nonsustained ventricular tachycardia and documented exertional syncope. All patients were informed about the experience and potential risk of ASA at the institutional site and subsequently in agreement with the procedure, which was performed by interventional experts experienced in this disease. Details of the ASA technique have been described in several previous reports. 4,11,12 2.2 | Data collection and follow-up Check-up of a large proportion of patients was conducted in outpatient clinic visit including the following programs: symptoms, the occurrence of clinical events, ECG, and echocardiographic parameters, while others by means of telephone contact and online communication regarding clinical data offered by local institutional sites. For patients who died outside hospitals, communication with next of kin was implemented to ascertain the cause of death.

| Definitions and study endpoints
The primary endpoints were all-cause mortality and HCM-related death.
In addition, the implementation of this current study in mildly symptomatic patients with HOCM was also to determine: (1) Differences in symptomatic improvement and the occurrence of new-onset atrial fibrillation (AF) between two groups; (2) Predictors of all-cause mortality. The causes of HCM-related death consisted of SCD, congestive heart failure and AFrelated stroke. Periprocedural death occurring within 30 days after ASA was also considered as HCM-related death. SCD was defined as instantaneous and unexpected death within 1 h after witnessing collapse in patients who were in a previously stable clinical condition, or nocturnal death with no antecedent history of worsening symptoms. Congestive heart failure was defined as death that occurred cardiac decompensation stage along with disease developing, and may be accompanied by pulmonary edema or cardiogenic shock.
Normally distributed continuous variables were expressed as mean ± SD. The independent Student's t test was used for the comparison between two groups, while paired Student's t test was used within the same group. Non-normally distributed continuous data were expressed as median (interquartile range [IQR]). The Chi square test was used to analyze categorical variables summarized as numerals (percentages). Survival analysis was performed by Kaplan-Meier method and subsequently survival difference between two groups was compared using the Log-rank test. The prognostic predictors of clinical events were determined by Cox regression model. First in a univariable model, potential variables having an influence on the endpoint were evaluated, including: age; sex; ASA; AF at the last checkup and some echocardiographic parameters. Second, variables with a p < 0.10 were entered into a backward stepwise multivariable analysis. Moreover, probability SCD at 5 years was also added to Cox regression model, and the HCM Risk-SCD formula was introduced in the 2014 ESC guidelines. All tests were two sided, and a p value of <0.05 was considered statistically significant.

| Baseline characteristics
Baseline clinical and echocardiographic characteristics of the study population are shown in Table 1

| Clinical outcomes
Clinical and echocardiographic characteristics of the last check-up are depicted in Table 1 in the course of HCM leads to the impairment of life quality and the increased mortality. 17 AF-related stroke is one of the main causes of adverse prognosis in HCM patients. 18 In our study, the incidence of new-onset AF following ASA was significantly lower than that of patients in the medical group ( Evidence from the Euro-ASA registry indicated that LVOT gradient at the last check-up was one of independent predictors of allcause mortality in highly symptomatic patients treated with ASA. 6 Similarly, Veselka et al. 20 suggested that residual LVOT obstruction (LVOT gradient≥30 mmHg) after ASA increased the risk of cardiovascular mortality events in highly symptomatic patients with HOCM.
According to multivariable regression analysis in our study, resting The safety of ASA procedure has been clarified in several studies. 14,21,22 The rate of mortality and permanent pacemaker implantation during periprocedural period was 1.3% and 10.0%, respectively. 22 In our current study, the rate of mortality (1.7%) during periprocedural period was similarly low compared with the result of the Euro-ASA registry. 14 The possible reason why the incidence of permanent pacemaker implantation was low is that volume of injected alcohol during ASA was conservative (1.9 ± 0.9 ml). Likewise, injection of large volumes of alcohol during ASA is not recommended, as it is associated with a higher incidence of permanent pacemaker dependency. 23 In addition, scar formation after ASA is closely associated with fatal arrhythmias, and the risk of SCD is a concern. In this study, there were two patients who died of SCD in the ASA group, which was similar to the medical group.
This study was a retrospective, nonrandomized and single-center study with a small sample, and the results were limited. First, analysis may be influenced by selection and referral bias because a part of patients from referral cannot represent the general HOCM population. Second, the efficacy and safety of ASA was cautiously extended, since patients were treated in our center experienced in HCM management in China. Third, comorbidities (e.g., coronary artery disease) were known to affect patient survival and may be more remarkable in larger sample or longer follow-up time. This study did not evaluate the impact of relevant aspects. Fourthly, the management of AF patients, for example, indications for medical therapy including anticoagulation have changed significantly during the inclusion period. In our study, AF patients took a relatively small proportion and adhered to taking warfarin as the anticoagulant therapy. Therefore, the anticoagulant therapy considered as a confounding factor has little effect on the prognosis. Finally, overall survival of patients enrolled in our current study was not compared with expected survival of an age-and sexmatched Chinese general population.

| CONCLUSION
This registry suggests that mildly symptomatic patients with HOCM treated with ASA have comparable survival to that of medically treated patients. Furthermore, ASA has advantages on the improvement of NYHA class and the reduction of LVOT gradient, with a lower occurrence of new-onset AF. Therefore, ASA could be considered as an alternative therapy for mildly symptomatic patients with HOCM intolerant to medication.

CONFLICT OF INTEREST
The author declares there is no potential conflicts of interest. Writing -review &editing: All.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.