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 10 th Avenue New York, NY 10019 Phone: 212 523 7370 Fax: 212 523 7765 Email: [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 l l l l l l lt t t t t t t Ho Ho Ho Ho Ho Ho Hosp sp sp sp sp sp spit it it it it it ital al al al al al al C C C C C C Cen en en en en en ent t t t t t t N Y Y Y Y Y Y Y k k k k k k k NY NY NY N NY NY N niversity, College of Physicians & Surgeons, New York, NY C D niversity , College of Physicians & Surgeons, New York, NY Cur ur ur r rrent add d d dre ess s s: Va Va Va Va Val l ll l l ey y y y y H He e ealt lth h Ca C Care e e e e S S S S Sys y y te em m m, R Rid d d d dg ge g g g wo wo wo wo wood od od d d, NJ N N N N D D by guest on February 9, 2018 http://circheartfailure.ahajournals.org/ Downloaded from by guest on February 9, 2018 http://circheartfailure.ahajournals.org/ Downloaded from by guest on February 9, 2018 http://circheartfailure.ahajournals.org/ Downloaded from by guest on February 9, 2018 http://circheartfailure.ahajournals.org/ Downloaded from
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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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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
n in 2005, matattttttchcccccc
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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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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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by guest on February 9, 2018http://circheartfailure.ahajournals.org/
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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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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by guest on February 9, 2018http://circheartfailure.ahajournals.org/
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 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
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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