Download Primary Prophylaxis of Sudden Death in Hypertrophic

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Primary Prophylaxis of Sudden Death in Hypertrophic
Cardiomyopathy, Arrhythmogenic Right Ventricular
Cardiomyopathy, and Dilated Cardiomyopathy
GEORGE J. KLEIN, M.D., F.R.C.P.C., F.A.C.C., ANDREW D. KRAHN, M.D., F.R.C.P.C., F.A.C.C.,
ALLAN C. SKANES, M.D., F.R.C.P.C., RAYMOND YEE, M.D., F.R.C.P.C., F.A.C.C.,
and LORNE J. GULA, M.D., F.R.C.P.C.
From the Division of Cardiology, University of Western Ontario, London, Ontario, Canada
Primary Prophylaxis of Sudden Death. We present an evidence-based overview of primary prevention of sudden cardiac death. Several recent studies have provided important data regarding pharmacologic
and device-based therapy for patients with conditions that confer high risk for sudden death. A rational approach to these therapies, with emphasis on implanted cardiovertor defibrillators, is discussed. (J Cardiovasc
Electrophysiol, Vol. 16, pp. S28-S34, Suppl. 1, September 2005)
implanted cardiovertor defibrillator, primary prevention, sudden death, cardiomyopathy
Introduction
Dilated Cardiomyopathy
The implantable cardiovertor defibrillator (ICD) is arguably one of the most significant developments in cardiology of the last century. Its efficacy in secondary prevention
after resuscitation from cardiac arrest is well established.1-3
Primary prophylaxis is more difficult, requiring accurate risk
stratification with good sensitivity, specificity, and predictive
accuracy, a goal that has proved elusive. Considerable data
are available for patients after myocardial infarction (MI)4,5
and consensus exists about the general efficacy of ICD in patients with prior MI and poor left ventricular function. Several
randomized trials have also established the basis for the management of patients with idiopathic dilated cardiomyopathy
(DCM) and symptomatic left ventricular dysfunction.6-8 Unfortunately, cardiac arrest can occur with virtually any cardiac
disorder. Large randomized trials may not be feasible if the
disease in question is relatively uncommon, or if reasonably
useful risk stratifiers for arrhythmic death are not available. A
definitive trial may also be unrealistic in a disease that is detected at an early age, where the meaningful clinical endpoint
is lifetime prevention of sudden death. The risk of sudden
death can be estimated, albeit imperfectly, from cohort data
in disorders such as hypertrophic cardiomyopathy (HCM),
arrhythmogenic right ventricular cardiomyopathy (ARVC),
and the repolarization syndromes, but considerable judgment
is required with the acceptance of uncertainty in ICD decisions since the annual risk of sudden death is generally low
and most patients do well for many years or a lifetime. The
decisions are even more problematic in other disorders such
as myotonic dystrophy, amyloid heart, valvular disease, and
others where rigorous data are lacking and often difficult to
obtain.
The 5-year mortality for dilated cardiomyopathy is approximately 20% with sudden death accounting for 8–51%
of deaths.9,10 Although ventricular arrhythmias are common,
sudden death is infrequently the first clinical event.11,12 The
risk of cardiac arrest is highest in patients with advanced
cardiac disease who also have the highest overall mortality.
Bradycardia, pulmonary embolus, pulseless electrical activity, and other mechanisms account for up to 50% of sudden
deaths in advanced heart failure.13-15 Predictors of sudden
death unfortunately also predict total mortality and reflect
severity of disease9 but are less useful with less severe disease.16,17 Syncope portends a higher risk of sudden death
regardless of the proven etiology of the syncope18,19 and patients with ICD implantation receive benefit comparable to
secondary prevention patients.18-21 Nonsustained ventricular tachycardia (VT) correlates with disease severity but is
ubiquitous with severe left ventricular dysfunction.15,22,23 Inducibility of VT predicts sudden death,18 but failure to induce
VT is not reassuring.22,24-26 Microvolt T wave alternans has
been shown to predict sudden death with DCM with modest
predictive accuracy.27 Idiopathic dilated cardiomyopathy has
multiple etiologies but is familial in at least 40% of cases.28-31
Unfortunately, genetic information is not currently useful for
risk stratification.
The treatment of DCM is currently individualized. Beta
blockers and angiotensin converting enzyme inhibitors are
standard therapies that improve overall mortality and sudden
death.32,33 Amiodarone is generally preferred for treatment
of symptomatic arrhythmias because of a favorable hemodynamic profile and low proarrhythmic potential. The impact
of amiodarone in preventing sudden death has been controversial34,35 but amiodarone was not superior to placebo in the
largest and best controlled trial available, the SCD-HeFT.8
The ICD is superior to amiodarone for secondary prevention of ventricular tachycardia and fibrillation.1-3,36 There
have been several primary prevention trials. The cardiomyopathy trial (CAT) enrolled patients with recently diagnosed
DCM but was terminated early due to a lower than expected
mortality.37 This was a relatively small study with 50 patients in the ICD arm and 54 in the control group. The 5-year
Address for correspondence: George Klein, M.D., F.R.C.P.C., F.A.C.C.,
London Health Sciences Center, University Campus, 339 Windermere
Road, London, Ontario, Canada N6A 5A5. Fax: (519)434-3278; E-mail:
[email protected]
doi: 10.1111/j.1540-8167.2005.50116.x
Klein et al.
follow-up showed fewer deaths in the ICD group versus
control (13 vs 17, respectively). The AMIOVERT study38
enrolled 103 patients with dilated cardiomyopathy, ejection fraction (EF) <35, and nonsustained ventricular tachycardia, and was stopped early with no difference between
amiodarone and ICD groups. The Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE)
enrolled 458 patients with nonischemic cardiomyopathy,
EF <35%, and frequent premature ventricular complexes
(PVCs) or nonsustained ventricular tachycardia. After 2
years, mortality was 13.8% with usual therapy versus 8.1%
in the ICD group, amounting to a 5.7% absolute reduction
and a 34% relative risk reduction with ICD implantation (P
= 0.06).39 The Sudden Cardiac Death in Heart Failure Trial
(SCD-HeFT) compared amiodarone, ICD, and usual therapy
in 2,521 patients with coronary artery disease or nonischemic
cardiomyopathy who were in New York Heart Association
(NYHA) class II or III heart failure with ejection fraction
<35%.8 The median follow-up was 45.5 months. The total
mortality in the medical group was 7.2% per year over 5 years
with a risk reduction of 22% in the ICD group versus placebo,
confidence intervals, 0.62–0.96, P = 0.007. There was no
mortality difference between the amiodarone and placebo
groups. Forty-eight percent of patients had nonischemic cardiomyopathy with a 27% reduction in mortality versus 23%
for ischemic patients. The trials for primary prophylaxis of
sudden death in DCM did not generally include functional
class 1 individuals.6 It is probable that dilated cardiomyopathy with EF less than 30 in NYHA class 2 and 3 patients will
become a class 1 or at least class 2A indication for prophylactic ICD with emerging guidelines both in the United States
and elsewhere.
Hypertrophic Cardiomyopathy
Most individuals with HCM are asymptomatic and the
first manifestation may be sudden cardiac death.40-45 Sudden
death is usually related to ventricular arrhythmia with triggers such as ischemia, outflow obstruction, or atrial fibrillation.42-44,46 Sudden death is less frequently due to bradycardia.47 The annual mortality from HCM has been estimated to
be as high as 6%,42,48,49 but community-based studies suggest
a range of 1% or less.40,50-54 This relatively low incidence creates a challenge for risk stratification.55 Features suggesting
higher risk of sudden death have been derived from observational studies.50,56-65 In one study, 23 of 480 patients died
suddenly over a mean follow-up of 6.5 years.66 The risk of
sudden death was directly related to septal wall thickness,
with essentially no mortality over 20 years with wall thickness less than 20 mm and almost 40% for wall thickness
of 30 mm or greater. Patients with such extreme wall thickness were relatively young and frequently asymptomatic. The
degree of outflow obstruction has been shown to predict cardiovascular but not sudden death.62,66 MRI67 and CT68 have
been suggested to be helpful in assessing the extent of disease and predicting sudden death. Sudden death in one or
more family members has been suggested to signify higher
risk.42,48,69 Specific genetic abnormalities have been associated with increased risk70-74 and the role of genetic testing is
likely to increase.70 Syncope45,75-78 has been correlated with
increased risk of sudden death. A flat or hypotensive response
to upright or supine exercise testing has been shown to predict
sudden death albeit with low predictive value. A normal blood
Primary Prophylaxis of Sudden Death
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pressure response identifies a low-risk group.46,79-81 Spontaneous ventricular tachycardia40,77,82-84 has been associated
with higher risk while VT induced in the electrophysiology
laboratory has been associated with a higher risk in one85 but
not other studies.86,87 A consensus document of the American
College of Cardiology and European Society of Cardiology
has categorized the known risk factors for sudden death as
“major” and “possible” in individual patients.76
Major risk factors for sudden death in HCM
1. Cardiac arrest (ventricular fibrillation)
2. Spontaneous sustained ventricular tachycardia
3. Family history of premature sudden death
4. Unexplained syncope
5. LV thickness greater than or equal to 30 mm
6. Abnormal exercise blood pressure
7. Nonsustained spontaneous ventricular tachycardia
Possible risk factors in individual patients
1. Atrial fibrillation
2. Myocardial ischemia
3. LV outflow obstruction
4. High-risk mutation
5. Intense competitive physical exertion
The major independent risk factors may prove to be a
measure of the extent of disease and the underlying genetic
abnormality. The absence of risk factors identifies a low-risk
group, and a single risk factor has limited positive predictive
value. Stratification based on incorporation of multiple risk
factors would likely improve positive predictive accuracy.88
Symptomatic patients are generally treated with beta
blockers or verapamil.42,48 Atrial fibrillation can be especially
problematic89,90 with sudden clinical deterioration. Amiodarone is most widely used in this context.89,91 Medical therapy has not been proven to be beneficial in prevention of
disease progression in the asymptomatic individual.48 Optimal medical therapy and control of comorbidities may reduce
the risk of sudden death although this has not been proven.
The ICD has been used in patients with cardiac arrest, sustained VT, or VF with a high percentage of patients receiving appropriate discharge during follow-up at a rate of 11%
per year.92 ICD implantation in the subgroup for primary
prophylaxis on the basis of perceived high risk for sudden
death resulted in a lower rate of appropriate discharge of 5%
per year.92 Nonrandomized studies have suggested a role for
amiodarone to prevent sudden death,91,93 while other studies
have suggested symptomatic improvement but no reduction
of sudden death.94,95 Amiodarone is unlikely to be superior
to the ICD for this purpose, and a randomized study comparing the two is unlikely be done in the light of recent studies
favoring the ICD in multiple patient groups.96 Most asymptomatic patients with HCM have a relatively benign course.
The ICD decision is individualized in patients considered to
be at high risk for sudden death.17,97,98 Patients with multiple
risk factors, especially severe septal hypertrophy (>29 mm)
and those with sudden death in close relatives appear to be at
a sufficiently high risk to merit consideration of prophylactic
ICD therapy.
Arrhythmogenic Right Ventricular Cardiomyopathy
Arrhythmogenic right ventricular cardiomyopathy (AVRC) (“right ventricular dysplasia” arrhythmogenic cardiomyopathy) is suspected in patients with right ventricular
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Journal of Cardiovascular Electrophysiology
Vol. 16, No. 9, Supplement, September 2005
arrhythmias (LBBB) or relatives with known ARVC.99,100
It is an eclectic cardiomyopathy that often presents with arrhythmias rather than right heart symptoms. Patients may
have simple ectopy, sustained and nonsustained VT, or ventricular fibrillation. ARVC needs to be ruled out when VT
originates from the RV outflow region. Idiopathic RV outflow VT is usually not associated with the ECG abnormalities
seen with ARVC, is more common in women, and is exercise
induced or initiated by isoproterenol more frequently than
by programmed stimulation.101,102 The ECG in ARVC frequently shows precordial T wave inversion over V1-V3 and
a QRS duration greater than 110 msec.101 Low-voltage potentials following the QRS (Epsilon waves) are characteristic
but infrequent and late potentials are observed on the signalaveraged ECG in greater than 50% of individuals.101,103,104
Unfortunately, sudden death is frequently the first manifestation of the disease.105-107 A standardized diagnostic scheme
has been formulated to establish a clinical diagnosis on a
point score basis.83 The annual incidence of sudden cardiac
death has ranged from 0.08% to 9% in several modest-sized
cohorts.99,100,108,109 In an autopsy series of ARVC patients,
24 of 27 patients died suddenly and 3 died of congestive
heart failure.110 Sudden death occurs relatively frequently
but not exclusively during exercise or stress.111 In one Italian
series, up to 25% of sudden deaths in athletes were related
to ARVC.112 Sudden death is more probable in individuals
with grossly visible RV abnormalities but may occur in those
with only microscopic abnormalities and no obvious RV enlargement.113 RV dilation, precordial repolarization abnormalities, and LV involvement have been associated with sudden death.99,114 There may be “malignant” genotypes.108,115
Sudden death in family members intuitively suggests a higher
risk of sudden death and men may be more at risk of early
mortality than women.115
The treatment of ARVC is individualized. The ICD has
been used in patients with unexplained syncope, sustained
VT, or VF with a high incidence of appropriate shocks.115-118
Although there are no randomized trials in ARVC, the situation is sufficiently “similar” to other disease states with wellestablished indications.3,98 ICD in individuals with a family
history of sudden death or a genetic basis known to be “malignant” is intuitively compelling with data to support this
practice.115 The ICD may be offered to asymptomatic individuals on an individualized basis based on the presence of the
above risk factors. Antiarrhythmic agents including class 1C
agents and amiodarone both alone and in combination with
beta-blocking drugs have proved useful for symptomatic ventricular tachycardia.101,119 Radiofrequency ablation is useful
for eliminating problematic tachycardias120 but may not prevent sudden death. Ongoing cohort registries may identify
risk factors to better predict patients who will benefit from a
prophylactic ICD.
The Challenge of Primary Prophylaxis
The ICD is a wonderful tool of undoubted efficacy.
Nonetheless, the device remains relatively expensive and results in personal challenges and some morbidity for individuals. Guidelines are helpful but are a just a starting point. It
is of dubious wisdom to implant devices in those individuals
whose meaningful lifespan is limited by comorbidities where
it is arguably at best not useful and may actually just change
the mode of death to one less palatable. It takes courage and
wisdom to make these judgments in cooperation with patients and their families. It may be useful to conceptualize
actual outcomes in a series of 100 patients implanted with
a device. For example, the SCD-HeFT clearly demonstrated
a 23% risk reduction or an absolute reduction of 7.2 deaths
over the 5 years of the study in patients with functional class
2 and 3. In our hypothetical 100 patient cohort followed over
5 years, one might expect approximately 7 or 8 to have their
life saved at the end of this time. One might also expect 29
to be dead in spite of the device and 64 to not have used
the device appropriately or to have complications and lifestyle issues related to it. Since the annual benefit is relatively
low, it takes years for meaningful benefit to be apparent. It
would logically follow that extrapolating the results to patients with limited life expectancy due to advanced age and
comorbidities is of questionable effectiveness even if such
patients may technically be candidates by guidelines (Fig.
1). Conversely, patients relatively well with a low annual risk
but otherwise long estimated longevity such as with “less
severe” heart failure, the repolarization syndromes, ARVC,
Figure 1. Average annual event rates over 3
years are illustrated, determined by extrapolation from published Kaplan-Meier curves
from clinical trials. During initial 3 years in
ICD trials, subjects generally experienced annual mortality rates of 7–15% with a 1–5%
absolute risk reduction with ICD therapy. Patients with HOCM 121,122 and ARVD123,124
demonstrate a slightly lower annual mortality rate without therapy, with an appropriate
shock rate that well exceeds the mortality rate
supporting the notion that not all appropriate
ICD therapies are life saving.
Klein et al.
and hypertrophic cardiomyopathy are at risk for many years
and may well benefit. Decisions in these individuals and their
families are often fraught with great anxiety, and the ICD can
bring reassurance in borderline cases. The key to useful application and expansion of this important technology will be
good judgment, clear communication, patient selection, and
hopefully further data to provide more focal assessment of
risk and benefit.
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