treatment of obstructive hypertrophic cardiomyopathy symptoms

1

Treatment of Obstructive Hypertrophic Cardiomyopathy Symptoms and

Gradient Resistant to First-Line Therapy with Beta-Blockade or Verapamil

Sherrid et al: Obstructive HCM Resistant to First-Line Therapy

Mark V. Sherrid, MD; Aneesha Shetty, MD, MPH; Glenda Winson, RN;

Bette Kim, MD; Dan Musat, MD*; Carlos L. Alviar, MD; Peter Homel, PhD;

Sandhya K. Balaram, MD; Daniel G. Swistel, MD

Hypertrophic Cardiomyopathy Program, St. Luke’s-Roosevelt Hospital Center, Columbia

University, College of Physicians & Surgeons, New York, NY

*Current address: Valley Health Care System, Ridgewood, NJ

Correspondence to Mark V. Sherrid, MD 1000 10th Avenue New York, NY 10019 Phone: 212 523 7370Fax: 212 523 7765Email: [email protected]

DOI: 10.1161/CIRCHEARTFAILURE.112.000122

Journal Subject Codes: Heart failure:[11] Other heart failure, Treatment:[118] Cardiovascular pharmacology, Cardiovascular (CV) surgery:[39] CV surgery: other

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Abstract

Background—There is controversy about preferred methods to relieve obstruction in hypertrophic

cardiomyopathy (HCM) patients still symptomatic after beta-blockade or verapamil.

Methods and Results—Of 737 patients prospectively registered at our institution, 299 (41%) required

further therapy for obstruction for limiting symptoms, rest gradient 61+45, provoked gradient 115+49

mmHg, followed 4.8 years. Disopyramide was added in 221 (74%) and pharmacologic control of

symptoms was achieved in 141 (64%). Overall, 138 (46%) patients had surgical relief of obstruction

(91% myectomy), and 6 (2%) alcohol septal ablation. At follow-up resting gradients in the 299

patients had decreased from 61+44 to 10+25 mmHg, p<0.0001; NYHA class decreased from 2.7+0.7

to 1.8+0.5, p<0.0001. Kaplan-Meier survival at 10 years in the 299 advanced-care patients was 88%

and did not differ from non-obstructed patients (p=0.28). Only one patient had sudden death, a low

annual rate of 0.06%/year. KM survival at 10 years in the advanced-care patients did not differ from

that expected in a matched cohort of the US population (p=0.90).

Conclusions—Patients with obstruction and symptoms resistant to initial pharmacologic therapy with

beta-blockade or verapamil may realize meaningful symptom relief and low mortality through stepped

management, adding disopyramide in appropriately selected patients, and when needed, by surgical

myectomy.

Key Words: hypertrophic cardiomyopathy, surgery, pharmacologic treatment

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Left ventricular outflow tract (LVOT) obstruction at rest or after physiologic provocation occurs in

approximately 2/3 of patients with HCM, usually from systolic mitral-septal apposition1 and is

associated with adverse outcomes2. In symptomatic obstructed patients pharmacologic therapy is

the first-line approach. Using recommendations from the previous two decades we selected

treatment paths for patients with obstruction resistant to first-line pharmacotherapy with beta-

blockade or verapamil, based on their cardiac pathology, risk stratification for sudden death, and

symptoms3-7. There have been case series describing the response of obstructed patients to

treatments such as disopyramide, surgery, alcohol ablation, or dual chamber (DDD) pacing with

short AV delay3,7-10. However, given the heterogeneous presentation and anatomy of obstructive

HCM, and the wide age range of presentation from youth to old age, a “one size fits all” approach

cannot be applicable or practical6,11.

Methods

St. Luke’s-Roosevelt Hospital Center (SLR) has offered organized consultation services for

referred HCM patients since 1985; we have maintained a prospective registry of evaluated

patients. The current report includes all patients initially evaluated from 1985 to June 30, 2011.

The diagnosis of HCM was confirmed by demonstrating a hypertrophied (> 15 mm) non-dilated

LV in the absence of a cause of hypertrophy sufficient to cause that observed.

For each patient heart failure symptoms were assessed based on NYHA classification and

the Minnesota Living with Heart Failure Questionnaire (MLHF QOL). All patients signed

informed consent approved by the IRB of SLR for use of their clinical data for research purposes

and for annual questionnaire or scripted telephone follow-up. If patients could not be reached,

their survival was determined by interrogation of the social security death index.

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Echocardiography: Echocardiograms with standard imaging planes were performed at initial

evaluation and last follow-up. Continuous wave Doppler was used to measure LVOT gradient

from the apical 5 and 3 chamber views to record maximum velocity parallel to the systolic

LVOT flow. Care was taken to separate LVOT signal from that of mitral regurgitation (MR).

Gradient was measured during 3 Valsalva maneuvers and after standing. The simplified

Bernoulli equation was used to calculate gradient. After 1994 capable patients underwent

treadmill testing with Bruce protocol and had gradients acquired after exercise1.

Echocardiographic maximal LV wall thickness was measured from parasternal long axis and

short axis views3. Since 2004 cardiac magnetic resonance imaging was performed in patients

with ambiguous or suboptimal echocardiograms3. The length of the anterior mitral valve leaflet

was measured on the echocardiographic apical three chamber view in diastole from the tip of the

anterior leaflet to the insertion of the non-coronary aortic cusp12,13.

Stepped treatment

After year 2000 all patients were stratified for sudden death (SCD) risk4. Patients who were

deemed to be at increased risk for SCD because of prior sustained ventricular tachycardia or

resuscitated ventricular fibrillation, massive thickening >30 mm, sudden death in first degree

relative, unexplained syncope, or non-sustained ventricular tachycardia in patients < 30 years old

were counseled about the benefits and risks of the implanted defibrillator (ICD) and, given

consent, were implanted3,4. ICD follow-ups were obtained either at our own clinic or through

questionnaires and scripted phone calls. The nature of ICD interventions were confirmed by

analysis of stored electrograms in all cases by a SLR attending electrophysiologist.

Based on their treatment path patients were divided into 3 groups.

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Group 1: Obstructed, beta-blocker or verapamil. These patients had LVOT obstruction >30 mm

Hg, either at rest or after physiologic provocation and symptoms could be managed with beta-

blocker or verapamil, or they were asymptomatic and required no pharmacologic therapy. In all

obstructed patients vasodilator medications for hypertension or renal disease were stopped3.

Group 2: Obstructed, advanced-care: These obstructed patients required advanced-care because

they had both limiting symptoms and had rest or provoked gradients >50 mm Hg despite

treatment with beta-blockade, verapamil, or both. Group 3: Patients without obstruction at rest or

after provocation.

The treatment paths for the 299 obstructed, advanced-care patients are shown in Figure 1.

1) The largest group of these obstructed, advanced-care patients were started on

disopyramide. Time-release disopyramide 250 mg 2x/day was added to either beta-blocker or

verapamil. If patient weight was <100 pounds, or for mild degree of renal failure (creatinine 1.3-

2.0) initial dose was decreased to 200 mg 2x/day. Disopyramide was initiated during a 3 day

hospitalization under continuous ECG monitoring7,14. Additionally during hospitalization, daily

ECGs were performed to assess the expected QTc prolongation. In patients with an inadequate

echocardiographic response (resting LVOT gradient > 40 mm Hg after 2 days) the dose of

disopyramide was titrated up to 600 mg/day and beta-blockade was optimized to a resting heart

rate of 50-60 bpm.

After hospital discharge patients were seen after 3 weeks and then every 4 months in follow-

up for drug titration and 12 lead ECG monitoring. Follow-up visits were at our center in 85% of

patients; the remaining patients saw their local cardiologists. Regular disopyramide dosing was

continued unless QTc exceeded 525 msec in patients with initial normal QRS duration, or 550-

560 msec in patients with initial intraventricular conduction delay14. Patients who experienced

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improvement in their limiting symptoms were continued on pharmacologic therapy. To mitigate

vagolytic side effects of dry mouth or constipation, sustained-release pyridostigmine, a

cholinesterase inhibitor, was administered as needed in doses of 90-180 mg, 2x/day. This allows

continuation of adequate disopyramide dosing15. Patients who had no symptom improvement, or

who experienced drug side effects were referred for surgical septal myectomy, unless they had

significant medical co-morbidity or refused surgery3.

2) Selected patients were referred for surgical septal myectomy without an intervening

disopyramide trial. These patients had SAM, mitral-septal contact but also had either: a)

significant coexisting conditions that required combined surgical repair. b) Selected patients who

had the combination of anterior mitral leaflet length > 33 mm plus resting gradients > 85 mm Hg

were also referred to surgery without disopyramide trial because of our experience that such

patients have a mechanical problem that does not respond to pharmacotherapy13. c) patients with

symptomatic prostatism (hesitancy, dribbling) were referred for surgery as disopyramide is

contraindicated in this setting. Depending on patient choice, surgery was performed at SLR in

80% of patients while the remaining 20% had their operations at other North American centers16.

Operative technique and results of the resect-plicate-release (RPR) modification of the standard

Morrow myectomy as performed at SLR have been described previously10. Individual

components of the operation are extended myectomy, horizontal plication of the anterior mitral

leaflet and release of the papillary muscles. Components are selectively applied, as necessary,

depending on scrutiny of the pre-operative echocardiogram, intraoperative transesophageal

echocardiography and direct surgical inspection.

3) DDD pacing with short AV delay and complete ventricular capture was applied sparingly

and selectively in specific conditions3.

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Dyslipidemia was treated with appropriate pharmacologic therapy, usually a statin17.

Statistical Methods

Normally distributed data are described as mean ± SD and categorical data as frequency

(percent). Baseline characteristics were compared by ANOVA. In patients who first received

disopyramide and then septal reduction therapy, gradients after disopyramide are reported both

before the intervention, and after the intervention. Changes in gradient and symptoms were

compared using paired t-tests. Cox proportional hazards test was used to compare survival in the

3 treatment groups. Survival rate for the obstructed advanced-care group was compared with

survival rate published by the CDC for the general US population in 2005, matched for age of

diagnosis, gender, and race18. A Microsoft Excel 2007 program (Microsoft Inc. Redmond WA)

developed by Finkelstein19 for calculating a one sample log rank test was used to test for a

difference. SAS 9.1 (SAS, Inc. Cary, NC) was used for all other analyses.

Results

Patients and treatment paths: Of the 737 patients in the registry, 14 patients who received

surgical myectomy before our initial evaluation were excluded from survival analysis. The whole

group of registry patients, n=723 were followed for median 4.5 years (IQR=2.2-7.6). In groups 1,

2 and 3 the follow-ups were 3.9 years (IQR=1.9-6.4), 4.8 years (IQR=2.6-8.1), and 4.9 years

IQR=(2.1-8.1) respectively. Characteristics of the 723 patients in the 3 treatment groups are

shown in Table 1. There were 299 obstructed advanced-care patients (group 2) who had

gradients and symptoms unresponsive to beta-blockade or verapamil requiring further treatment.

The interquartile age range was wide, 45.8-68.2 years. They had been treated before initial

evaluation with beta-blockade (235) or verapamil (64) or both (38). Compared to the other 2

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groups the obstructed advanced-care patients were older, more frequently had rest obstruction,

had greater maximal wall thickness, were more symptomatic, and more frequently had atrial

fibrillation (AF) and coronary disease (CAD). The treatment paths for the advanced-care group

are shown in Figure 1.

Change in gradient depending on the treatment selected is shown in Table 2 and in the Figure

in the supplemental online material. In the whole patient group (n=299) resting gradient

decreased from 61 +44 to 10 +23 mm Hg (p<0.0001). Table 3 shows the change in symptoms by

final therapy selected. Symptom management was an iterative process. Patients who did not

respond to disopyramide were offered septal reduction. There was improvement in NYHA

classification and MLHF QOL after the final treatment selected in all patient groups.

Disopyramide was administered to 221 patients, mean daily dose 501 ±30 mg, followed for

5.1 +3.8 years. This dose was higher than that used in the multicenter registry of obstructive

HCM patients reported in 2005 (432 +181 mg, p< 0.0001) 7. To mitigate the vagolytic effects of

disopyramide 117 (53%) patients received pyridostigmine timespan, at least temporarily. The

221 patients who were begun on disopyramide might otherwise have been candidates for septal

reduction; but, 141 (64%) were successfully continued on therapy and followed 4.5 +3.6 years

with a favorable response without need for septal reduction. In the whole group of 221 patients

in whom it was used, disopyramide lowered resting gradients, from 63 +45 to 25 +32 mmHg

(p<0.0001). In the 141 patients (64%) successfully managed with pharmacologic therapy

including disopyramide, without need for septal reduction, the average resting gradient was 18

mmHg at final evaluation demonstrating long-term gradient reduction; additionally, symptoms

improved as shown in Table 3. In contrast, in the 80 patients (36%) who eventually required

septal reduction, the final gradients achieved with pharmacologic treatment were lower than

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initial values (p<0.0001), but were inadequate to control symptoms, and averaged 40 mmHg,

higher than in the patients who could be managed without septal reduction therapy (p<0.0001)

Table 2.

Septal reduction: In 63 obstructed HCM patients surgical myectomy was judged to be the best

treatment without a disopyramide trial. Table 4 shows the characteristics of these patients. The

balance of the septal reduction patients, n=80, were those who received disopyramide but failed

to respond adequately or had drug side effects and who then underwent septal reduction (75

surgical, and 5 alcohol ablation). The 138 patients who underwent surgery were followed for 5.5

±3.6 years; 125 (91%) patients had surgical septal myectomy, and 13 (9%) had mitral valve

replacement for calcific disease. In this series only 6 (2%) patients received ablation, 3 because

of severe medical co-morbidities and 3 because of patient choice. As expected, gradient

reduction was most complete in the surgical group, gradient at follow-up 3 +9 mmHg and

symptoms improved in parallel as shown in Table 3.

Survival: Survival follow-up was complete in 718 (99.3%) patients; 5 (0.7%) patients were

lost to follow-up (only 1 in the advanced-care group). Survival comparison between the 3 HCM

groups, graphed in Figure 2, showed no difference in survival between the 3 groups; 10 year

survival was 87% in group 1, 88% in group 2, and 85% in group 3 (p=0.28).

Deaths in the obstructed advanced-care group: Of the 299 patients there were 25 deaths over

the 5.6 years of follow-up. Fifteen deaths were judged to be non-cardiac, while 10 deaths were

from cardiovascular cause including 4 patients who died after cerebrovascular accidents (mean

age 81, 3 with AF). In the obstructed advanced-care group there was only one sudden death, in a

77 female heavy smoker who died suddenly 7 years after beginning disopyramide. Annual rate

of sudden death was very low 0.06% /year in the whole advanced-care group. There were no in-

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hospital deaths in our surgical patients, and long-term survival was 95% at 10 years. In the 221

disopyramide-treated patients the annual rate of sudden death was 0.1% /year.

Comparison with age-matched US survival: There were 25 deaths observed in the

advanced-care group while 24 were expected based on the general population. As shown in

Figure 3 the observed rate of survival for the 299 obstructed advanced-care patients did not differ

from the expected survival in the general United States population, p = 0.90.

Device therapy: In the obstructed advanced-care group 56 (19%) patients had ICD

implanted at SLR for primary prevention, and 3 for secondary prevention. ICD patients were

followed up 6.1 +3.5 years. There were appropriate discharges in 3 (5%) patients implanted for

primary prevention. These discharges occurred in 2 patients at 2 months and 5 years after

surgery, respectively, and in one patient 2 years after disopyramide. Two patients implanted for

secondary prevention (both with mid-LV obstruction and an apical akinetic chamber also had

appropriate discharges).

Lethal, and potentially lethal arrhythmias: In the whole advanced-care group events

included sudden death (1 pt), successfully resuscitated ventricular tachycardia (1 pt), post-

operative prolonged non-sustained ventricular tachycardia (1 pt) and appropriate ICD discharge

in primary prevention patients (3 pts). The combined annual rate of lethal and potentially lethal

arrhythmic events was 0.4% /year.

Of the patients with ICD 38 patients were also DDD paced with short AV delay for gradient

reduction. An additional 19 patients had DDD pacemaker inserted specifically for gradient

reduction, but without an ICD. Thus, overall, 57 (19%) of the obstructed advanced-care patients

were DDD paced for gradient in combination with pharmacologic therapy and were followed for

6.3 ± 3.9 years. Only ten (18%) of these patients required surgical myectomy for control of

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gradient and symptoms. At follow-up in the paced patients there had been 8 deaths, 4 non-

cardiac and 4 cardiovascular deaths.

Complications in the 299 obstructed-advanced care patients are shown in Table 5.

Discussion

A relatively common clinical dilemma that confronts physicians caring for obstructive HCM

patients is how to manage patients whose symptoms and gradients are resistant to first-line therapy

with beta-blockade or verapamil. These patients represent a subset of HCM patients who often are

referred for advanced care3,16. In this study we applied a stepped approach to this widely

heterogeneous group, in whom therapy was individually tailored for sudden death prevention and

for symptom relief. We found that such an approach can result in a meaningful improvement in

functional status, very low sudden death mortality, and overall mortality that did not differ from

that expected in a matched cohort of the general U.S. population. Additional major observations

from this experience are 1) patients whose symptoms and gradients can be successfully controlled

by disopyramide and beta-blockade have a low mortality, and a very low sudden death mortality.

A similar disopyramide/beta blockade experience has recently been reported by Ball and

colleagues11. In their report, patients who responded to conservative pharmacologic therapy with

symptom relief had an 87% HCM-related survival at 10 years. In their report >150 patients

achieved symptom relief with disopyramide but without septal reduction. In the present report a

similar number achieved symptom relief without septal reduction and together, this experience

numbers nearly 300 patients with excellent survival. In both reports patients who responded to

pharmacotherapy were maintained on their successful regimens, and those who did not were

referred for septal reduction. 2) In the present study, carefully selected patients preferentially

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underwent surgical myectomy3,4. There were no in-hospital deaths in our 138 surgical patients, and

survival at 10 years was 95% with no late sudden deaths.

Stepped management: In our therapy we were guided by additional maxims: 1) all patients

regardless of obstruction and category had formal risk stratification for sudden death; in patients

with high risk implanted defibrillators were placed; 2) patients with concomitant cardiac pathology

like severe CAD, moderate aortic valve disease, or MR from intrinsic mitral abnormalities more

than SAM, had surgery sooner in their course17; 3) We have observed that patients who fail to

respond to disopyramide have a combination of adverse physiologic and anatomic features: both

very high resting gradients and long anterior mitral leaflets as described above. Patients with this

combination (~15% of considered individuals) have a mechanical problem; in recent years we

have referred patients with this combination directly to surgery if they fail beta-blockade

/verapamil, without an intervening disopyramide trial, particularly if they are less than 45 years of

age13,14. 4) patients otherwise were treated by adding disopyramide to their pharmacologic

regimen, usually with beta-blockade5-7,11,14. 5) For elderly or frail patients resistant to

disopyramide DDD pacing with short AV delay was preferred. Disopyramide was continued

because of the previously reported positive synergy between DDD pacing and disopyramide20.

Survival: Overall, mortality in our advanced-care obstructed patients was low; survival did not

differ from the expected mortality observed an age, gender and race matched cohort of the United

States population. Kaplan-Meier survival at 10 years was 88%. These results are similar to that

previously reported when surgical therapy was employed for resistant cases8. Mortality has

previously been reported higher in obstructive HCM patients than in patients without obstruction2.

In sharp contrast, we observed no difference in mortality between our advanced-care obstructed

patients and our non-obstructed patients, Figure 2. There was only one sudden death in the 299

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patients in the obstructed advanced-care group, a very low annual incidence of 0.06% / year. The

combined annual rate of sudden death, resuscitated ventricular tachycardia and appropriate ICD

discharge in primary prevention patients was low, 0.4% /year. We posit that these low rates of

mortality, sudden death, and potentially fatal arrhythmias occurred because of the stepped

treatment herein described that yielded a mean final resting gradient of 10 mmHg21.

There are few randomized trials of treatments in HCM22. In their absence, below are comments

pertinent to our choices for therapy.

Disopyramide: Introduced by investigators from Toronto, disopyramide is often administered

to patients whose next option would be septal reduction therapy should pharmacologic therapy

fail3, 5-7,11,14. We found a 60% reduction in resting gradient in the 221 patients initiated on

disopyramide and a corresponding improvement in symptoms. Of the patients begun on

disopyramide who might otherwise have been candidates for septal reduction, 141 nearly two

thirds continue on pharmacologic therapy 4.5 years without need for septal reduction.

Disopyramide’s particular efficacy in obstructive HCM is due to its marked negative inotropic

effect compared to other agents23,24, and that it has no vasodilator effect25. In direct head-to-head

comparisons of its effect on gradient, it is more potent than verapamil or beta-blockade24. It is

usually given in combination with beta-blockade to blunt the exercise-related rise in gradient, for

synergistic negative inotropic effect, and to provide AV delay should AF occur. Despite its type I

antiarrhythmic effects, proarrhythmia with disopyramide is very rare in patients with HCM; we

found a very low rate of sudden death mortality, 0.1% /year. This low sudden death incidence may

most likely be attributed to gradient lowering, though we cannot exclude a beneficial intracellular

metabolic effect. Nevertheless, we continue the surveillance described above in our disopyramide-

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treated patients3,7. We did not observe any organ toxicity from disopyramide, no renal, hepatic,

hematologic or central nervous system adverse effects. This makes it suitable for long-term use.

We administered a higher dose disopyramide in the present cohort than in the multicenter

registry of 2005 (501 vs. 432 mg/day)7 because there is a prominent dose-response relationship

with disopyramide, with more effective gradient reduction at higher dose14. Pyridostigmine

controlled-release (Mestinon timespan) administered with disopyramide attenuates side effects

such as dry mouth and constipation and we offer it, as needed, to all patients15. Half of our patients

received pyridostigmine timespan at least temporarily . The safety of the combination in

obstructive HCM is shown in the present study.

Though disopyramide is a mainstay of pharmacologic therapy at UK and Canadian programs

with national scope6,11 it has seen less use in the US. For example, it had been prescribed in 11% of

patients before surgical myectomy in one study8 and in 11% of patients before ablation in

another26. The current experience is unique in the US as 74% of patients received disopyramide, at

higher dose than previously, and pyridostigmine sustained release was used to control vagolytic

side effects.

Surgical septal myectomy: A third of our patients failed their trial of disopyramide/beta-

blockade, or had adverse side effects, and required septal reduction. Surgical septal myectomy is

the “gold standard” treatment for such patients and has been performed for 40 years3,16. In recent

years because of improved understanding about the cause of mitral-septal contact, appreciation of

the role of the mitral valve and the papillary muscles, and because of improved surgical technique,

excellent outcomes are now reported with in-hospital mortalities <1% and excellent long term

survival3,8,10,27,28. In the 80% of patients operated at SLR we applied a patient-tailored

individualized modification of the classic Morrow myectomy that we have termed the Resect-

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Plicate-Release operation. The surgical techniques of the RPR repair grew out of prior surgical

innovations27 and its results have been reported previously10. A unique aspect of this surgical

cohort is the application of horizontal anterior mitral leaflet plication in selected patients with long,

redundant slack mitral anterior leaflets. Within the advanced-care group a subgroup analysis of

survival between aggressive-pharmacologic and surgical patients would not be a valid comparison

because of selection bias: the pharmacologic group included more patients with advanced age and

severe comorbidities.

Alcohol septal ablation: The myectomy vs. alcohol ablation controversy cannot be resolved

by a prospective randomized trial3,22,26. ten Cate found late sudden death and appropriate ICD

discharge in 14% of ablation patients after 5.4 years, substantially higher than in their surgically-

treated patients29. From the prospective data in the current study, we can at least conclude that

excellent overall resuIts can be obtained by a strategy that reserves alcohol ablation for patients in

whom surgical myectomy is contraindicated, or when informed patients are reluctant to undergo

surgery.

DDD pacing with short AV delay, though not a primary therapeutic option for young patients

with obstructive HCM30 has a limited positive role in selected patients such as the elderly or those

already implanted with an ICD3. There is a synergistic beneficial effect for gradient reduction

when DDD pacing is used with disopyramide20.

Treatment of obstructive HCM has evolved over the 26 years encompassed in this study.

Comparing the first with the second half of the time period under consideration, the annual number

of surgical myectomies performed for resistant symptoms nearly tripled, the number of ICD

implants more than doubled, and DDD pacing for gradient reduction declined, to the benefit of our

most severely affected patients.

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Conclusion: Patients with obstruction and symptoms unresponsive to initial pharmacologic therapy

with beta-blockade or verapamil may realize meaningful symptom relief and low mortality through

stepped management by adding disopyramide in appropriately chosen patients, and when needed, by

surgical septal myectomy.

DisclosuresNone.

References

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NGNGNGNGNGNGNG,,, , , , , KuKuKuKuKuKuKuvivivivivivivin n n n n n n JTJTJTJTJTJTJT, , , NNNNNNNis prrrrrrredededededededomomomomomomominininininininananananananantlt

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guideline for the diagnosis and treatment of hypertrophic ca

larrrrr oooooutututututflflflflflowowowowow tttttract obstruction. CiCiCiCiircrrcr ulation. 20000006;6666 114:2232-223OOOOOliiiiivotto III, BBBBBetetetetetocococococchchchchchi iiii S,S,S,S,S, CCCCCasasaseyeyeee SAAA, LeLeLeLeLessssssssssererererer JJJJR,R,RR,R LLLLLosososososi iiii MAMAMAMAMA, CeCeCeCeCecccccct vvvvveeenee tricularaar outuutflowowowww traaaaactctt obsbstrucuuctiiiiiononononon ooon ccclinnnicaalaaa outttcocococc mme innn athyhyhyhyhy. N NNNN EnEnEnEEnglgllgll JJJJJ MMMMMeddddd. 2020202020033333;3;3;3;334848484848:2:2:2:29595959595 3-33330303030303. aron BJ, Bonow RRRRO,O,O,O,O, DDDDDeaeaeaeaeararararr nin JJAAAAA,, ,, FiFFFF fefer rrr MAMAMAMAMA,,,,, Link MS, Naidu

n nn SRSRSR, RaRaRaakokokokowswswswskikikiki HHHH, , , SeSeSeSeS ididididmamamaman n n n CECECECE, ,,, ToToToT wbwbwbwwbinininnn JJJJJA,A,A,A,, UUUUdedededelslslslssonononon JJJEEE, YYYaaagguiuidedelilinene fforor tthehe ddiaiagngnososisis aandnd ttrereatatmementnt ooff hyhypepertrtrorophphicic ccaa


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11. Ball W, Ivanov J, Rakowski H, Wigle ED, Linghorne M, Ralph-Edwards A, Williams WG, Schwartz L, Guttman A, Woo A. Long-term survival in patients with resting obstructive hypertrophic cardiomyopathy comparison of conservative versus invasive treatment. J Am Coll Cardiol. 2011;58:2313-2321.

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13. Musat D, Joshi R, Obeleniene R, Bangalore S, Winson G, Castaneda V, Musat C, Chaudhry FA, Sherrid MV. Impact of acute response of obstructive hypertrophic cardiomyopathy to oral disopyramide and correlates of response. J Am Coll Cardiol. 2008;51:A61 Abstract.

14. Sherrid MV, Arabadjian M. A primer of disopyramide treatment of obstructive hypertrophic cardiomyopathy. Prog Cardiovasc Dis. 2012;54:483-492.

15. Teichman SL, Ferrick A, Kim SG, Matos JA, Waspe LE, Fisher JD. Disopyramide-pyridostigmine interaction: Selective reversal of anticholinergic symptoms with preservation of antiarrhythmic effect. J Am Coll Cardiol. 1987;10:633-641.

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prognosis of patients with hypertrophic cardiomyopathy who have epicardial coronary artery disease. Circulation. 2003;108:2342-2348.

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20. Minami Y, Kajimoto K, Kawana M, Hagiwara N, Sherrid MV. Synergistic effect of dual chamber pacing and disopyramide in obstructive hypertrophic cardiomyopathy. Int J Cardiol. 2010;141:195-197.

21. McLeod CJ, Ommen SR, Ackerman MJ, Weivoda PL, Shen WK, Dearani JA, Schaff HV, Tajik AJ, Gersh BJ. Surgical septal myectomy decreases the risk for appropriate implantable cardioverter defibrillator discharge in obstructive hypertrophic cardiomyopathy. Eur Heart J. 2007;28:2583-2588.

22. Olivotto I, Ommen SR, Maron MS, Cecchi F, Maron BJ. Surgical myectomy versus alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Will there ever be a randomized trial? J Am Coll Cardiol. 2007;50:831-834.

23. Sherrid MV, Pearle G, Gunsburg DZ. Mechanism of benefit of negative inotropes in obstructive hypertrophic cardiomyopathy. Circulation. 1998;97:41-47.

24. Kajimoto K, Imai T, Minami Y, Kasanuki H. Comparison of acute reduction in left ventricular outflow tract pressure gradient in obstructive hypertrophic cardiomyopathy by disopyramide versus pilsicainide versus cibenzoline. Am J Cardiol. 2010;106:1307-1312.

25. Epstein SE, Rosing DR. Verapamil: Its potential for causing serious complications in patients with hypertrophic cardiomyopathy. Circulation. 1981;64:437-441.

26. Nagueh SF, Groves BM, Schwartz L, Smith KM, Wang A, Bach RG, Nielsen C, Leya F, Buergler JM, Rowe SK, Woo A, Maldonado YM, Spencer WH, 3rd. Alcohol septal

Fisher JD. Disisisisisisisooininininininnererererererergigigigigigigicc c ccc c sysysysysysysympmpmpmpmpmpmptototototototommmmmmm1987878787777;1;1;1;1;1;1;10:0:0:0:0:0::636363636363633-3-3-3-3-3-3-66664666

Hypertrophic cardiomyopathy centers. Am J Cardiol. 2009;10mmen SR, Nishimura R Gersh BJ, Berger PB, Ta k AJ. Af re

a6DM Muzikansky A Schoenfeld DA Comparing survival of

Hypepepepepertrtrtrtrtrororororophpppp icicicicic cardiomyopathy cececeecentnnnn ers. Am J CaCCCC rdiol. 2009;10mmmmmmmmmmen SR,R,R,RR NNNNNisisisisishihihihihimumumumumurarararara RRRRRA,AAAA GGGGGere shssh BBBBBJ,J,J,JJ BBBBBererererergegegeg r r r rr PBPPBPBP ,, ,, TaTaTaTaTajijijjijik k k kk AJAJAJAJAJ. Af pppppaataaa ients wwwitth hhypppeeere troppppphihiic cacardddiiomymymymymyopopopo aathhhy wwhohohohoho havavvavve eepiccaaare. CiCiCiCiCircrcrcrcr ulululululatatatttioioiooon.nnnn 222220000003;3;3;3;3 10101010108:8:8:8::23232323234242424242-2-2-2223434343434888.88 oyert DL, Xu J, MuMuMuMuMurprprprprphyhyhyhyhy SSSSSL.LLL DDDDeaeaeaaaththththths:ss:s FFFFFinininnalalalalal dddddata for 2005. Na666:1:1:1-1-1-1202020. DMDM MuMuziziziiikakakakk nsnskykykykk AAAA SSSSchchchhhoeoenfnfnfffelelelllddddd DADADADAD CoCoCoCC mpmpararinininii gg susurvrvivivivalalal oofff


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ablation for the treatment of hypertrophic obstructive cardiomyopathy. A multicenter North American registry. J Am Coll Cardiol. 2011;58:2322-2328.

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28. Iacovoni A, Spirito P, Simon C, Iascone M, Di Dedda G, De Filippo P, Pentiricci S, Boni L, Senni M, Gavazzi A, Ferrazzi P. A contemporary European experience with surgical septal myectomy in hypertrophic cardiomyopathy. Eur Heart Journ. 2012;33:2080-2087.

29. ten Cate FJ, Soliman OI, Michels M, Theuns DA, de Jong PL, Geleijnse ML, Serruys PW. Long-term outcome of alcohol septal ablation in patients with obstructive hypertrophic cardiomyopathy: A word of caution. Circ Heart Fail. 2010;3:362-369

30. Maron BJ, Nishimura RA, McKenna WJ, Rakowski H, Josephson ME, Kieval RS, assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy a randomized, double-blind, crossover study (M-PATHY). Circulation. 1999;99:2927-33.


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Table 1. Baseline characteristics of 723 patients with HCM

Variable All HCM n=723 Group1, Obstructed Beta Blocker or Verapamil n=210

Group 2, Obstructed advanced care n=299

Group 3, Non-obstructed n=214

p value

Age 53.8 ±17 54.1 ±18 56.7 ±15 48.4 ±17 <0.001

Gender (%m) 57 65 51 59 0.003 Rest LVOT Gradient mmHg 33 ±42 26 ±31 61 ±45 1 ±4 <0.001 %Obstructed at rest 41 38 71 0 <0.001 Provoked gradient mmHg 74 ±64 89 ±41 115 ±49 2.5 ±10 <0.001 %Obstructed at rest or after provocation 68 100 100 0 <0.001

NYHA class 2.3 ±0.8 2.1 ±0.9 2.7 ±0.7 1.7 ±0.8 <0.001

MLHF QOL 27 ±24 22 ±23 37 ±23 19 ±21 <0.001

MWT (mm) 22 ±6 20.8 ±6 22.7 ±6 22.4 ±7 0.02

Syncope (%) 26 21 28 28 0.16 FH SCD first degree relative (%) 16 21 14 22 0.10

NSVT (%) 26 21 31 26 0.28

BB (%) 66 64 76 55 <0.001

CCB (%) 22 26 21 18 0.14

FH of HCM (%) 39 36 35 48 0.005

AF (%) 19 12 24 19 0.002

CAD (%) 10 8 15 5 <0.001

EF (%) 64.6 ±13 63.5 ±16 66.5 ±9 63.3 ±13 0.33

BB=beta blocker; EF=ejection fraction; FH=family history; MWT= Maximal LV wall thickness; NSVT= non-sustained ventricular tachycardia

0

±0.8 2.1 ±0.9 2.7 ±0.7 1.7 ±0.8

±24 22 ±23 37 ±23 19 ±21

±

21 28 28

±0.0.000.8 888 8 2.1 ±0.9 2.77. ±0.7 1.7 ±0.8

±222224 4 4 44 22222 ±2323232323 3777 ±2222233333 1919191919 ±211111

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Table 2. Gradient reduction after treatment in 299 patients with advanced-care for obstructive HCM

Treatment Initial resting gradient mmHg

Gradient at follow-upmmHg

Interim gradient after disopyramide but before septal reduction n=80 p value

All obstructed pts receiving advanced care, n=299 61 ±44 10 ±23 <0.0001

Disopyramide, all pts n=221 63 ±45 25 ±32* <0.0001

Disopyramide without septal reduction n= 141† 59 ±46 18 ±31 <0.0001

Septal reduction after disopyramide=80§ 69 ±41 7 ±17** 40 ±27‡

‡< 0.0001 **<0.0001

All surgical pts n=138 65 ±42 3 ±9# <0.0001

*Gradient reported here includes that measured before intervention in 80 patients who had subsequent septal reduction. †43 (30%) patients had DDD pacing for gradient as well20.§surgery in 75 and septal reduction in 5. **final gradient after septal reduction in 80 patients who first received disopyramide. ‡interim gradient after disopyramide but before septal reduction, lower compared with their initial gradients, but higher than the final gradients in the 141 patients who could be managed without septal reduction, both p< 0.0001. #less than final gradient in 221 patients treated with disopyramide (p<0.0001), and less than final gradient in 141 patients treated with disopyramide but without septal reduction (p<0.0001)

27‡

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Table 3. Improvement in symptoms in the obstructed, advanced-care group

Treatment NYHA Initial Evaluation

NYHA Last Visit p value

MLHF QOL Score Init Evaluation

MLHF QOL Last Visit p value

All patients n=299 2.7 ±0.7 1.8 ±.5 <0.0001 37 ±23 27 ±23 <0.0001

All surgical patients n=138 2.7 ±0.7 1.7 ±.5 <0.0001 39 ±23 27 ±22 <0.0001

All disopyramide-treated pts without septal reduction n=141

2.7 ±0.6 1.9 ±.5 <0.0001 40 ±23 27 ±23 <0.0001


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Table 4. Characteristics of 63 patients with LVOT obstruction due to SAM,mitral-septal contact referred directly for surgery without a trial of disopyramide

* including 5 patients with syncope and 1 with cardiogenic shock. MVR=mitral valve replacement; RVOT=right ventricular outflow tract

Characteristics # of patients

Concomitant cardiac surgery (n=23)

Coronary bypass 9

MVR to relieve MR due to intrinsic abnormality more than SAM, i.e., calcified leaflet 7

Aortic valve replacement for moderate aortic valve disease 4

Aortic root replacement for aortic aneurysm 1

RVOT myectomy for RV outflow obstruction 1

ICD lead extraction 1

Unfavorable anatomy thought not likely to respond to any pharmacologic therapy; long anterior mitral leaflet and high resting gradient * 20

Contraindications (n=11)

Symptomatic prostatism 6

Amiodarone therapy for AF 5

Patient choice 7

Psychosocial 2

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Table 5. Complications of therapy in 299 patients in the obstructed, advanced-care group

Class of therapy, number of patients treated

Complication Number of patients

Outcome

Surgical,n=138

Large ventricular septal defect and early post-op heart failure

1 Required reoperation for complete closure, NYHA I outcome

Post-operative stroke 1 Disability

Post-operative TIA 1 Complete resolution

Large Pericardial Effusion 4 (3%) Pericardial windows with complete resolution

Post-operative respiratory failure in patients with pulmonary disease

2 Prolonged ICU course

Heart block 7 (5%) Permanent pacer

Wound infection 2 Resolved with drainage and antibiotics

Disopyramide, n=221

Torsade de pointes in female, age 82 with 96 mmHg resting gradient who developed diarrhea-induced hypokalemia.

1 ICD discharge terminated arrhythmia which completely subsided after K+ repletion. Disopyramide resumed

Heart block (age 88) 1 Permanent pacemaker

Urinary hesitancy (age 53) Urinary retention (age 88)

11

Discontinued diso

Device Therapy ICD, n=59; DDD pacemaker n=24

Tamponade 2 Pericardial window with complete resolution

Inappropriate shockInappropriate ATP

12 (20%) 1

Specifically targeted responses

ICD infection 1 System extraction

PrPrPrPrPrPrProlololololololononononononongegegegegegegeddddddd

h

ws

Torsadddde eeee dedededede pppppoioioioiointntntntn eseseseses iiiin nnn fefefefefemamamamamalelelelele, agagagagageeeee 8282828282 1111 ICICICICICDDDDD disch

HeHeHeHeHeararararartttt blblblblblooocoo kkkkk 7 (5(5(55(5%))))) Permanen

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Figure Legends

Figure 1. Treatment paths in 299 obstructed advanced-care patients. ASA=alcohol septal ablation; Ant.

Leaf=anterior leaflet of mitral valve; DDD paced=AV sequential paced with short AV delay; Diso =

diso; verap = verapamil; *43 (30%) of the 141 patients who were successfully treated with

disopyramide were DDD paced as well.

Figure 2. Kaplan Meier plot comparing survival in 3 groups of HCM patients. Survival in the

obstructed advanced-care patients did not differ from non-obstructed patients.

Figure 3. Kaplan Meier plot comparing observed survival in the obstructed advanced-care group

(n=299, solid line) versus the expected survival based on 2005 US survival matched for age, sex

and race (dashed line).

US survival maaaaaaatctcttttt


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Homel, Sandhya K. Balaram and Daniel G. SwistelMark V. Sherrid, Aneesha Shetty, Glenda Winson, Bette Kim, Dan Musat, Carlos L. Alviar, Peter

First-Line Therapy with Beta-Blockade or VerapamilTreatment of Obstructive Hypertrophic Cardiomyopathy Symptoms and Gradient Resistant to

Print ISSN: 1941-3289. Online ISSN: 1941-3297 Copyright © 2013 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation: Heart Failure published online May 23, 2013;Circ Heart Fail.

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Supplemental Material

Figure Legend

Echocardiographic resting LVOT gradients in 299 patients in the obstructed advanced-care

group at initial evaluation and at last measurement after treatment. In the patients who received a

disopyramide trial, but then required septal reduction, interim gradients obtained just before the

invasive intervention are shown as well.

treatment of obstructive hypertrophic cardiomyopathy symptoms

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