Original Contribution

Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy: Safe and Apparently Efficacious But Does Reporting of Aggregate Outcomes Hide Less-Favorable Results, Experienced by a Substantial Proportion of Patients?

Robert M. Cooper, MBChB, MRCP1,2;  Adeel Shahzad, MBBS, MRCP1,2;  James McShane2;  Rodney H. Stables, MA (Cantab), DM (Oxon), BM BCH (Oxon)1,2

Robert M. Cooper, MBChB, MRCP1,2;  Adeel Shahzad, MBBS, MRCP1,2;  James McShane2;  Rodney H. Stables, MA (Cantab), DM (Oxon), BM BCH (Oxon)1,2

Abstract: Aims. To describe individual and aggregate outcomes for patients undergoing alcohol septal ablation (ASA) for hypertrophic obstructive cardiomyopathy (HOCM). Methods. Retrospective case series reviewing all patients undergoing ASA at a United Kingdom tertiary referral center from 2000-2012. Aggregate and individual outcomes are described in terms of symptomatic and hemodynamic response. Results. Eighty-eight patients were reviewed. Alcohol was delivered in 84, with clinical status data available in 82 and hemodynamic data available in 74. All patients had resting or exercise stress left ventricular outflow tract (LVOT) gradient >50 mm Hg. Mean age was 60.3 ± 14.3 years. Follow-up period was 4.2 ± 3.3 years. Twenty-four patients (27%) required ≥2 procedures. Complete heart block was observed in 17%. New York Heart Association (NYHA) class pre ASA was 2.80 ± 0.46, improving to 1.92 ± 0.84 post ASA (P<.001). Fifty-eight out of 82 patients (71%) had improved NYHA class. Resting peak gradient was 99.80 ± 45.86 mm Hg. Post-ASA peak gradient fell to 23.77 ± 41.87 mm Hg (P<.001). Sixty-one out of 74 patients (82%) had successful treatment of LVOT gradient. A successful outcome in both symptomatic and gradient treatment was seen in 66% of patients. No patient who received alcohol suffered sudden cardiac death. Fifteen patients had implantable cardioverter defibrillator implantation; no appropriate therapy was delivered. Conclusions. ASA is safe, with few major complications. Aggregate outcomes are good, but can hide individual failure. There is a need to refine case selection, procedure planning, and performance to secure more uniform favorable outcomes. 

J INVASIVE CARDIOL 2015;27(7):301-308

Key words: alcohol septal ablation, hypertrophic cardiomyopathy, non-surgical septal reduction therapy, sudden cardiac death

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Hypertrophic cardiomyopathy (HCM) is an inherited disease, characterized by otherwise unexplained hypertrophy of the myocardium. It has an estimated phenotypic prevalence of 1 in 500.1 Basal septal hypertrophy, narrowing the left ventricular outflow tract (LVOT), contributes to the pathology underlying LVOT obstruction. This is exacerbated by a systolic anterior motion (SAM) of the mitral valve apparatus, which, on contraction, moves toward the hypertrophied septum. The prevalence of LVOT obstruction in HCM is 20%-30% at rest2 and up to 70% with provocation.3 LVOT obstruction is associated with greater levels of dyspnea, a greater incidence of stroke, and higher mortality.2 

First-line treatment in symptomatic HCM patients with obstruction is the introduction of negatively inotropic medications. For patients with refractory symptoms, septal myectomy is recommended as the invasive therapy of choice by the American College of Cardiology Foundation/American Heart Association guidelines for the treatment of HCM.4 Alcohol septal ablation (ASA) is an alternative, percutaneous intervention. ASA can reduce the size and contractility of tissue obstructing the LVOT and reduce SAM.5 This reduces LVOT gradients and improves symptoms in the majority of patients. Recent reports have suggested that improvement of LVOT gradients with ASA may improve prognosis.6,7

Several series have sought to describe outcomes following ASA.6-15 Meta-analyses of comparisons to surgical myectomy have also been reported, with comparable outcomes.16 In the main, results show an improvement in mean LVOT gradient and reduced symptoms of dyspnea and chest pain. There is very little reporting of individual patient outcomes; this may be because no criteria for defining individual success have been agreed upon. We sought to investigate aggregate outcomes and define the numbers and proportions of patients who experienced both improved LVOT hemodynamics and improved functional capacity. We also describe our observations of arrhythmic risk post ablation in this group.

Methods

Patient selection. All patients referred to our center for consideration of ASA from April 2000 to December 2012 were reviewed.  A diagnosis of HCM was made according to typical clinical, electrocardiographic, and echocardiographic features. 

All patients had resting or exercise stress peak LVOT gradient ≥50 mm Hg and basal interventricular septal diameter >15 mm. All were trialled on negative inotropes prior to ASA. Only those taken to the lab with the intention of delivering alcohol were included in this report. 

Eighty-eight patients were identified (mean age, 60.3 ± 14.3 years; 52% female). Twenty-one patients had underlying lung disease, 3 had suffered previous cerebrovascular accident. Ten patients had undergone previous percutaneous coronary intervention and 1 patient had previous ASA at another center with poor outcome. 

Statistical analysis. Continuous variables are presented as mean ± standard deviation. Statistical analysis was performed with SPSS v 20. NYHA class change and LVOT gradient were evaluated using Wilcoxon signed rank test. Peak VO2 was normally distributed; hence, a paired t-test was used. Mann-Whitney U-test was used to assess alcohol volume injected as a risk factor for complete heart block. Pearson’s correlation was used to compare alcohol volume injected to CK-MB release.

Results

Follow-up data are presented for a mean period of 4.20 ± 3.33 years from the index procedure (range 0.13-12.29 years).

Procedural details. All procedures except 1 were performed by the same operator. The procedure has been well described.17

A patient was taken to the catheterization laboratory with the intention of delivery of alcohol on 125 occasions. Alcohol was delivered in 109 procedures (87%). The mean volume of alcohol delivered was 2.24 ± 1.09 mL. Four patients could not receive alcohol at any procedure due to limitations identifying or instrumenting appropriate septal vessels. Reasons cited for withholding alcohol injection were: lack of angiographically identifiable septal; poor localization of myocardial contrast on investigation; or inability to access septal artery due to limitations of equipment. Twenty-four patients (27%) required two or more procedures due to unsatisfactory outcome (Figure 1). 

Sixteen patients (18%) required two procedures. One patient did not receive alcohol at the first procedure due to equipment limitations and subsequently received alcohol at a second procedure.  The other 15 patients received alcohol at the first procedure, but progressed to a further procedure because of unsatisfactory outcomes. Twelve of these 15 patients received a further dose of alcohol at the second procedure, and 3 patients did not have an identifiable septal artery by angiography to explore. 

Seven patients (8%) returned for a third procedure; all had received two doses of alcohol previously, but returned due to unsatisfactory outcomes. Two of 7 patients received a third dose of alcohol. Five patients could not receive alcohol due to lack of angiographically identifiable septal artery (n = 3) or inaccurate localization of myocardial contrast on injection (n = 2). 

One patient underwent four procedures. He received only one dose of alcohol. After failure to deliver alcohol at follow-up procedures, covered stents were delivered to the left anterior descending coronary artery. In 92 procedures, we had complete data for volume of alcohol injected and the subsequent CK-MB release. The correlation coefficient was 0.15, giving us an R2 value of 0.0240 (Figure 2). This indicates a poor relationship between volume of alcohol delivered and size of infarct. 

Periprocedural complications. New complete heart block (CHB) was observed in 17% of patients. Permanent pacemaker (PPM) implantation was required in 14 of 74 patients without preexisting cardiac rhythm management devices. Those with preexisting device had implantable cardioverter defibrillator (ICD) for primary prevention,6 or attempted right ventricular apical pacing with permanent pacemaker to treat LVOT gradients.4

No new CHB was observed in those with a preexisting device. The incidence of CHB reduced in later procedures; 9 of 14 occurred in the first half, versus 5 of 14 in the latter half. There was a trend toward higher volumes of alcohol injected in those who developed CHB (2.75 ± 1.68 mL vs 2.16 ± 0.95 mL), but this did not reach statistical significance (P=.24).

There were no procedural deaths. One inpatient death was reported following hemodynamic compromise as a complication of pacemaker implantation post ASA. Ventricular fibrillation (VF) was observed 3 hours after ablation in 1 patient; DC cardioversion was successful. Repeat angiogram revealed no reflow in the target septal artery only, with no other changes to coronary flow. Distal infarction of the inferior wall was observed on echocardiogram 6 months post procedure in 1 patient. Pericardial effusion without tamponade was seen in 1 patient. Neither required further treatment. 

Survival and risk of ventricular arrhythmia. Over the entire follow-up period, 15 of the 84 patients who received alcohol died. Survival rates at 1 year, 2 years, and 5 years were 96% (n = 68), 93% (n = 54), and 84% (n = 33), respectively (Figure 3).  

No patient who received alcohol suffered sudden cardiac death (SCD). Nine patients suffered cardiovascular death. One inpatient death was reported due to complications of PPM insertion post ASA. Heart failure was the cause of death in 6 patients; 4 of these had clinical evidence of decompensated heart failure with preserved ejection fraction before ASA. Myocardial infarction was reported as cause of death 9 years after ASA in 1 patient. Stroke was the cause of death in 1 case; this patient was in sinus rhythm. Non-cardiac death was reported in 6 patients. 

One episode of sustained ventricular tachycardia (VT) was seen 2 weeks after ASA. This was reviewed by independent electrophysiology specialists. Analysis of 12-lead ECG recordings suggested that the abnormal rhythm did not have a septal origin.  An ICD was fitted. Fifteen patients had ICD implantation; 6 were in situ prior to ASA. No appropriate therapy was delivered. Mean follow-up period between ASA procedure and last arrhythmia check was 3.08 ± 2.77 years. 

Symptomatic resolution. Eighty-two of 84 patients who received alcohol had satisfactory follow-up data for clinical assessment. NYHA dyspnea class pre ASA was 2.80 ± 0.46, improving to 1.92 ± 0.84 post ASA (P<.001). 

Cardiopulmonary exercise testing. Twenty-four patients had satisfactory pre-ASA and post-ASA cardiopulmonary exercise testing. Selection criteria were not standardized. Peak VO2 increased from 18.90 ± 4.45 mL/min/kg to 20.09 ± 5.73 mL/min/kg (P=.02), exercise time increased from 568 ± 214 seconds to 615 ± 216 seconds (P=.046). 

Echocardiographic parameters. Basal septal diameter in diastole decreased from 22.35 ± 5.08 mm to 17.2 ± 4.25 mm (P<.001) in 63 patients for whom data was available. Seventy-four of 84 patients had satisfactory pre-ASA and post-ASA echocardiographic assessment of LVOT gradient. 

Those with a resting gradient ≥50 mm Hg and those with a resting gradient <50 mm Hg but exercise stress or Valsalva maneuver gradient ≥50 mm Hg will be reported separately. Very few patients who had a resting gradient >50 mm Hg underwent stress testing as they already had an indication for treatment. We are therefore unable to accurately report the rest and exercise gradient in all patients. Assessment of efficacy in those who required exercise provocation to unmask a significant gradient after treatment was made under the same conditions. Amalgamating rest and stress gradients in reporting can be misleading, so outcomes will be separated.

Resting gradient 50 mm Hg. Sixty-one patients had a preprocedural resting gradient of ≥50 mm Hg. Peak gradient was 99.80 ± 45.86 mm Hg and median gradient was 90 mm Hg. Following treatment, peak gradient fell to 23.77 ± 41.87 mm Hg (P<.001) and median was 10 mm Hg (Figure 4).

Resting gradient <50 mm Hg with exercise stress or  Valsalva gradient 50 mm Hg. Thirteen patients were identified. Preprocedure resting peak gradient was 27.50 ± 14.0 mm Hg, peak stress gradient was 102.00 ± 49.57 mm Hg, and median of peak stress gradients was 89 mm Hg. Post-ASA stress and Valsalva gradients were grouped, as Valsalva has been shown to be equivalent to stress echocardiography post ASA.20 Post-ASA peak stress gradient was 16.92 ± 30.65 mm Hg (P<.001) and median value was 0. 

Assessment of failure of treatment. 

LVOT gradient. There are no established criteria for procedural success. For the purposes of this series, failure is defined as a persisting gradient of >50 mm Hg or failure to reduce the gradient by >50%. 

Preprocedure resting gradient 50 mm Hg. ASA was considered a success in 49 patients (80%). Failure to reduce the gradient to <50 mm Hg was noted in 9 patients (15%), treatment did not reduce the gradient by greater than one-half in a further 3 patients (5%). 

Preprocedure resting gradient <50 mm Hg with exercise stress or Valsalva gradient 50 mm Hg. ASA was considered a success in 12 patients (92%), and 1 failure (8%) to reduce the gradient to <50 mm Hg was observed. 

Dyspnea. Failure to improve symptoms of dyspnea was defined as failure to improve NYHA status ≥1 class. Fifty-nine patients (71%) improved; 16 patients (19%) improved by 2 NYHA classes, 43 patients (51%) improved by 1 NYHA class. Twenty-one patients (27%) had no difference, and 2 patients (2%) deteriorated from class III to IV. 

Combining clinical and echocardiographic outcome measures. A two-way matrix displays combined outcomes (Figure 5). Two-thirds of patients achieved a satisfactory outcome by both clinical and echocardiographic parameters. A total of 11% failed to achieve success by both clinical and echocardiographic criteria, while 7% achieved some improvement in symptom status (all improved by 1 NYHA category) with limited change in LVOT gradients. A total of 16% achieved resolution of LVOT gradient without change in symptom burden. One-half of this category suffered significant lung disease, 3/12 had COPD, and 3/12 had pulmonary fibrosis. 

Discussion

ASA appears to have few serious complications. The risk of complete heart block necessitating PPM implantation remains around 15%. Lower doses of alcohol and increased operator experience appear to reduce this risk; our rate of PPM implantation lowered in the second half of the observed period. The observed rate and pattern of pacemaker implantation from our group mirrors previously published reports over a similar time span.15,18 The rate is higher than some series that report on recent techniques,19 but includes patients treated up to 12 years ago when alcohol doses and PPM rates were much higher. While the ramifications of a pacemaker should not be dismissed, we must bear in mind right ventricular apical pacing can be an effective treatment to reduce LVOT gradients in some. Others require ICD implantation due to risk of SCD. The use of cardiac rhythm management devices in this group may have an independent value and is not necessarily a classic “complication.”

The fears regarding the pro-arrhythmic risk of an iatrogenic infarct do not appear to have been substantiated in medium-term follow-up. No significant burden of VT was seen in those with internal monitoring systems in our group. Many other studies have come to similar conclusions,6,7,14,20 while a smaller number claim an increased risk of ventricular arrhythmia.21

ASA improves LVOT gradients in most, but 14 of 74 patients still had significant gradients after the completion of treatment. Three went on to have surgical myectomy; others were unwilling to submit to cardiac surgery or were unsuitable because of co-morbidity. Four patients did not receive alcohol and are not included in the matrix. They must also be deemed as failures as they did not receive the intended treatment.

A further 12 patients had technical success in resolution of gradient by the specified criteria, but reported no improvement in dyspnea. Diastolic function can be improved by removal of the LVOT gradient and subsequent regression of afterload-dependent hypertrophy,22,23 but persisting diastolic dysfunction could account for a proportion of these ongoing symptoms. One-half of this cohort has significant lung disease. Our population is representative of a real-world patient group, in which symptoms are often multifactorial. 

Does aggregate outcome data mask a disappointing failure rate in individual patients? The failure of treatment for a significant proportion of patients could be easily overlooked in a classic aggregate analysis reporting pre-treatment and post-treatment mean values. The outcomes in our group when reporting in this manner are comparable to most medium-term series published (Table 1). When aiming to prove a treatment is efficacious, it is attractive to report that mean LVOT gradients improved from 99.9 mm Hg to 23.3 mm Hg (P<.001) post ASA, and mean NYHA class improved from 2.80 ± 0.46 to 1.92 ± 0.84 post ASA (P<.001). It is less attractive to hear that one-third of patients failed to benefit from the treatment in some respect. 

There is a continuing debate about the relative merits of surgical myectomy and ASA. Many centers cannot or do not offer myectomy and ASA is now the dominant option in terms of procedure numbers.24 Due to the relatively low international procedural volume of both interventions, it would be extremely difficult to perform a prospective randomized controlled trial to establish superiority in reducing mortality.25 We must therefore accept it is likely that cardiologists will continue to offer ASA as a treatment option, often in preference to myectomy. Nineteen centers in the United Kingdom offered ASA in 2011.26 As a result, we must strive to improve ASA to provide satisfactory treatment to a greater proportion of patients. 

The procedure went through an initial phase of rapid evolution. Over the last decade, a number of case series have reported similar results. It would appear that progress has stalled. There have been few substantial advances in procedural technique over recent years. We cannot afford to be complacent if we wish to make efficacy of the procedure more predictable and universal.

What limitations do we face with ASA? It is difficult to perform predictable, high-quality alcohol ablation due to inherent limitations associated with current techniques.

Identification of septal artery targets. We have very little information about myocardium supplied from invasive angiography. We rely on myocardial contrast injection into a potential target vessel and subsequent visualization of territory supplied from echocardiography – a process that depends on an initial selection from angiographic images alone. The optimum vessel may not be recognized, particularly if it is small or originates from an epicardial vessel other than the left anterior descending. A total of 5%-8% of patients do not receive alcohol because no septal vessel can be identified or instrumented.13,27 Some areas highlighted by contrast may be close to the target area of myocardium but not ideal.  These may be accepted as the best available option. This is less likely to have a significant long-term effect on LVOT hemodynamics.

Technical instrumentation. Some arteries cannot be injected because the operator is unable to safely balloon occlude the vessel. Accessing the artery with coronary wires can be difficult if many turns need to be negotiated, and the operator cannot introduce contrast or alcohol if the balloon kinks on bends.

Difficulty controlling infarct size. It is difficult to judge the size of myocardium supplied by the target vessel, and alcohol dose and injection rate are always an estimate. This is compounded by unpredictable tissue dwell time and absorption. The variable run-off of septal arteries is complicated by differential resistance in the distal perfusion beds; one septal artery can have a bifurcation with sub-branches to the right and left ventricular septum. The right-sided branch can drain directly into the ventricular cavity and therefore has a low resistance run-off; conversely, the left-sided branch enters densely packed, hypertrophied myocardium with high resistance to flow. Any fluid injected will therefore preferentially run toward the right side of the septum. There is an unpredictable response to the first injection aliquot – this may create no-reflow in the distribution bed, limiting delivery of subsequent injections. The volume of alcohol to be delivered can also be restricted by conduction system disturbance.

This is exemplified by the poor correlation between alcohol dose injected and CK-MB release observed in our data (Figure 2).

The demands of precision. In the ideal procedure, we seek to impact a very small target zone and need very precise localization. An infarction missing the ideal location by as little as 3 mm in any direction may render the procedure of no long-term value.

Prospects for improvement.

Procedural changes. There is a learning curve associated with performing ASA. Given the low number of patients undergoing the procedure, expert centers with high-volume operators should be responsible for ASA. Currently, 15 of 19 centers in the United Kingdom are registering <5 procedures per year.26 National databases will allow us to pool patient data and make conclusions about outcomes with greater security. 

There is significant promise in the prospect of computed tomography (CT)-guided ASA.28 CT offers the dual benefit of viewing angiography and structural detail, describing the course of septal vessels supplying the target area. This has the potential to change the approach to an individual procedure and target vessels with increased speed and accuracy. It remains to be seen if this translates into improved patient outcomes. 

Radiofrequency ablation in HCM has been performed,29 and has the advantage of independence from coronary anatomy. This method of septal reduction warrants further investigation. The use of microspheres and coils to occlude septal arteries has been explored in septal reduction,30,31 but has had limited interest since initial investigations. This process may mirror early use of coated stents.32 The process of ischemia is often insufficient to permanently damage myocardium due to the rich collateral supply to the septum.

Patient selection. A total of 16% of our patients had successful abolition of LVOT gradient, but had no improvement in symptoms. In these patients, it is likely that the LVOT gradient was not the predominant cause of dyspnea. Preprocedural cardiopulmonary exercise testing may allow us to decipher if the principal pathology is cardiac or respiratory. In some patients, diastolic dysfunction will persist after ASA. This could explain persisting symptoms, but current methods do not allow us to establish this in the screening phase.22

It is important to ensure the absence of HCM variants such as subaortic membranes, abnormal papillary muscle insertion, and primary MV abnormalities. These are not amenable to ASA and would be better treated with surgery. This is determined by a multidisciplinary team process involving cardiomyopathy doctors, imaging cardiologists, interventional cardiologists, and cardiac surgeons.

Treating cardiologists must also rule out HCM phenocopies that may respond to alternative treatment. While myocardial disease associated with ailments such as Noonan’s syndrome can be successfully treated,28 metabolic causes of hypertrophy and hypertensive heart disease should be treated differently. 

Conclusion

In experienced hands, ASA can be performed with a very low rate of procedural or subsequent complications. Many patients experience successful treatment. Up to one-third of patients are left with an unsatisfactory outcome after treatment with current methods. This important fact can be overlooked if we consider only aggregate outcome data. The procedure will continue to be recommended by cardiologists and be popular with patients. There is a need to continue to refine our case selection, procedure planning, and performance to secure more uniform favorable outcomes. 

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From the 1Institute of Cardiovascular Medicine and Science; and 2Liverpool Heart and Chest Hospital, Liverpool, United Kingdom.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted August 16, 2014, provisional acceptance given October 6, 2014, final version accepted October 15, 2014.

Address for correspondence: Dr Robert M Cooper, Liverpool Heart and Chest Hospital, Thomas Drive, Liverpool, L14 3PE, United Kingdom. Email: robcooper@doctors.org.uk

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