Download Prevention of Sudden Cardiac Death

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Prevention of Sudden Cardiac Death
DAVID S. CANNOM, M.D.
Good Samaritan Hospital, Los Angeles, California, USA
Sudden Cardiac Death. Although the annual incidence of sudden cardiac death (SCD) is dropping in
the United States, therapies for the patient who has survived a SCD episode or is at high risk of developing
SCD in the future are now well established. The implantable cardioverter defibrillator (ICD) has emerged
from a series of well done randomized clinical trials of the 1990s as providing a survival benefit in carefully
defined patient groups with low ejection fraction of any cause. Patients with either an ischemic or idiopathic
dilated cardiomyopathy and an EF ≤35% show a significant survival benefit with the ICD and maximal
medical therapy. Many challenging patients (e.g., those with long QT syndrome or Brugada syndrome) who
have a reasonably high incidence of sudden death have not been the subject of clinical trials involving the
ICD and therapy depends on risk stratification that is currently not completely agreed upon. An exciting
research frontier of the future will be those that attempt to integrate the appropriate role of the ICD with the
ability of chronic resynchronization therapy to enhance left ventricular function in the damaged ventricle.
(J Cardiovasc Electrophysiol, Vol. 16, pp. S21-S24, Suppl. 1, September 2005)
implantable cardioverter defibrillator, sudden cardiac death, heart failure, risk stratification
Sudden Cardiac Death: The Facts
Sudden cardiac death (SCD) is the leading cause of
mortality in the United States. It has been estimated that
200,000–450,000 sudden deaths occur annually.1 According
to the 2001 American Heart Association Statistical Handbook, there were 250,000 sudden deaths per year in the United
States. The National Center for Health Statistics stated that
in 1998 there were 719,456 cardiac deaths of which 456,000
were sudden. A study from Seattle between 1980 and 2000
showed a 34% decline in the annual incidence of treated cardiac arrests and a 56% decline for ventricular fibrillation (VF)
as the first identified rhythm.2 If these figures were applied
nationally, there would be 184,000 SCDs, at odds with earlier
estimates.
The incidence of SCD increases as patients age. Most of
the sudden deaths in the United States occur in patients 75
years and older with the greatest proportion being in patients
85 years and older.3 The vast majority of these deaths occur
among patients with symptomatic heart failure (HF) associated with reduced left ventricular function. Survival from
out-of-hospital cardiac arrest remains poor; it is estimated that
less than 20% of SCD victims will leave the hospital alive.4
Despite improvements in medical therapy, symptomatic HF
still confers a 20–25% risk of premature death in the first 2 12
years after diagnosis. Approximately 50% of these premature
deaths are sudden and attributable to ventricular tachycardia
(VT) or VF. The proportion of sudden death to total mortality
in HF associated with reduced left ventricular function has
not changed substantially between the era of the Framingham
data in the 1960s and today.
Recent clinical trials of implantable cardioverter defibrillators (ICDs) suggest that up to 50% of the deaths in patients
with left ventricular systolic dysfunction (LVSD) secondary
to coronary artery disease (CAD) are sudden or arrhythmic
Address for correspondence: David S. Cannom, M.D., Good Samaritan Hospital, 1245 Wilshire Building, 703, Los Angeles, CA 90017. Fax: 213-9770225; E-mail: [email protected]
doi: 10.1111/j.1540-8167.2005.50127.x
in nature.5 This incidence is lower in nonischemic etiologies of HF. As LVSD and symptom severity progress, overall mortality increases, yet the percentage of deaths classified as sudden decreases. In more recent clinical trials using
angiotensin converting enzyme (ACE) inhibitors and beta
blockers, NYHA class II patients have an annual mortality of
6% with approximately 60% of these deaths sudden. However, NYHA class IV patients have an annual mortality of
approximately 20% with only around 30% of these deaths
sudden.6
Attempts at identifying which HF patients are at an increased risk of SCD have met with limited success. To date,
there is still no single best measurement to identify which HF
patients will die from an arrhythmia rather than progressive
LVSD. Simple clinical markers such as greater age, degree
of LVSD, and severity of HF predict overall mortality but
have low specificity for the mode of death. Syncope has been
reported to be one specific clinical marker associated with
increased SCD.7-9 High frequency ventricular ectopy does
indicate a worse prognosis, yet controversy remains as to
whether this is predictive of the mode of death rather than a
reflection of the degree of LVSD.10,11 Inducibility of VT/VF
during electrophysiology testing (EPS) has a low sensitivity
in nonischemic or dilated cardiomyopathy (DCM) patients.
However, it does predict an increased risk of SCD in ischemic
CM but does not predict overall mortality.12,13
The Role of the ICD in Preventing SCD in CAD Patients
Several randomized, prospective trials have proven the
efficacy of the prophylactic ICD in improving survival in
patients who have survived SCD.14-16 A meta-analysis of
these trials reported that the ICD was associated with a 28%
reduction in the risk of death due almost entirely to a 50%
reduction in arrhythmic mortality.17 Patients with an ejection
fraction (EF) ≤35% derived the most benefit from the ICD.
These data provide strong evidence to support ICD use in all
patients who have survived SCD or sustained VT regardless
of the degree or etiology of HF.
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Vol. 16, No. 9, Supplement, September 2005
The inventors of the ICD (Drs. Mirowski and Mower) anticipated a prophylactic use for the ICD. They wrote in the
Archives of Internal Medicine in 1970 that “It is too early to
determine exactly the indications and contraindications for
the standby automatic defibrillator. . .. For use outside the
hospital this device might be implanted on a permanent base
in selected patients with CAD identified as belonging to highrisk populations.”18 Three well-designed primary prevention
trials in patients with reduced EF and CAD support a role
for the ICD in low EF patients.19-21 The Multicenter Automatic Defibrillator Implantation Trial (MADIT I) and the
Multicenter Unsustained Tachycardia Trial (MUSTT) examined patients with CAD, EF <40%, and inducible VT/VF
at EPS. MADIT I reported a 54% mortality reduction with
most of the benefit seen in patients with a history of HF
(∼40% of patients), EF <26%, or left bundle branch block
(LBBB).19 MUSTT showed a 27% risk reduction in SCD
solely attributed to the use of the ICD and not antiarrhythmic drug therapy.20 Approximately two-thirds of the enrolled
patients were either NYHA class II or III. MADIT II evaluated patients with CAD and EF <30% and did not require
inducibility of VT/VF by EPS. The ICD produced a 31% risk
reduction in overall mortality with the majority of the benefit occurring in patients with a QRS duration >120 msec.21
Approximately 60% of the patients were either NYHA class
II or III.
The SCD-HeFT Trial and the Dilated Cardiomyopathy
Patient
Previous small studies examining the role of prophylactic ICDs among patients with DCM have not defined the
role of the ICD. The Amiodarone versus Cardioverter Study
(AMIOVIRT) reported no mortality difference among patients with DCM and asymptomatic NSVT.22 Similarly, the
German Cardiomyopathy Trial (CAT) was stopped when interim statistical analysis suggested the impossibility of any
mortality difference emerging between ICDs and medical
therapy among patients with DCM diagnosed within 12
months of enrollment.23 The neutral results of these studies were due to inadequate sample size and the absence of a
requirement for symptomatic HF that in turn contributed to
lower than expected event rates. In contrast, the recently reported Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial, which randomized 458
patients with DCM, left ventricular EF <35%, and asymptomatic NSVT to ICD or conventional medical therapy,
demonstrated a 34% reduction in all-cause mortality in ICD
patients, but that did not reach statistical significance.24 A
post hoc analysis of NYHA class III patients showed a 67%
relative reduction in all-cause mortality, again showing that
patients with left ventricular dysfunction and more advanced
HF symptoms are most likely to benefit from ICD therapy as
in MADIT I.
The hypothesis of SCD-HeFT was to determine, by
intention-to-treat analysis, whether either ICD or amiodarone
reduces all-cause mortality compared with placebo in patients with ischemic or DCM, NYHA class II-III HF, and left
ventricular EF ≤35%.25 Event estimates were based on an
estimated 10% per year all-cause mortality rate in the control arm at a minimum follow-up of 2 12 years. The study was
powered to detect a 25% reduction in mortality in either the
ICD or amiodarone arm compared to placebo with α = 0.025
for each comparison. A total of 2,521 patients were enrolled
between 16 September, 1997 and 18 July, 2001 at 148 sites
in North America and New Zealand. Follow-up terminated
on October 31, 2003 yielding a median (25th percentile, 75th
percentile) follow-up duration of 40.8 (29.7, 53.0) months.
This long follow-up duration exceeds any prior study of ICDs
or drug therapy for the prevention of SCD.
Fifty-two percent of enrolled patients had an ischemic cardiomyopathy, 48% had a DCM, 70% were NYHA class II,
and 30% were Class III. A high standard for optimal medical
management of HF was maintained, which countered a historical criticism of prior ICD trials. At last follow-up, 87%
of patients were taking either an ACE or ARB, 78% were
taking beta blockers, 80% were taking diuretics, and 31%
were taking spironolactone. There were no important differences for baseline demographic variables, substrate, NYHA
class, or medical therapy among treatment groups with the
exception of slightly more beta-blocker use in class II (71%)
versus class III (64%) patients. Amiodarone was discontinued in 27.2% of patients during the study, consistent with
discontinuation rates observed in other studies for primary
prevention of sudden death and was similar to the discontinuation rate of placebo (22.5%).
The primary result of SCD-HeFT was a significant reduction in all-cause mortality with ICD therapy compared
to amiodarone or placebo. Five-year all-cause mortality was
35.8% in the placebo group, 34.1% in the amiodarone group,
and 28.9% in the ICD group (Fig. 1). Thus, ICD therapy conferred a 23% relative reduction in all-cause mortality (hazard ratio, [95% confidence interval] 0.77; P = 0.007). This
difference in mortality emerged within 18 months of enrollment and was sustained throughout follow-up. The majority
of deaths were cardiac (68%, similarly distributed among
treatment groups) and the mortality benefit of ICD therapy
was due entirely to a reduction in arrhythmic deaths (39% in
the placebo arm vs 20% in the ICD arm).
The mortality reduction among patients with ischemic cardiomyopathy approximates that observed in MADIT II and
serves to validate the findings of that study. More importantly,
the equivalent mortality reduction among patients with DCM
Figure 1. The Kaplan-Meier survival curve estimate of death from any cause
in the SCD-HeFT trial is shown. Note the 5-year reduction in mortality by
ICD of 23% compared to either placebo or amiodarone. This difference was
noted irrespective of the cause of the cardiomyopathy (ischemic or dilated)
but was limited to NYHA class II patients only.25 Reprinted with permission.
c 2005 Massachusetts Medical Society.
Copyright Cannom Sudden Cardiac Death
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Figure 2. This treatment algorithm was constructed based on available data from the secondary and primary prevention ICD trials.
Most high-risk populations encountered in everyday practice are included. Patients with
sustained VT and EF >35% have not been
studied in a randomized trial and the use of
EPS in this setting is the choice of the author.
Also, patients with nonsustained VT and an
EF >40% have not been randomized but historical data suggest they are at low risk. One
of the major challenges confronting clinicians
is how to integrate biventricular pacing into
the care of these patient groups both at initial implant and ICD change-out.26 Reprinted
c 1999 Ameriwith permission. Copyright can Medical Association.
demonstrates that the primary prevention mortality benefits
of ICD therapy seen in ischemic CM are identical to DCM
populations.
There were many peculiarities in the SCD trial design
that, while present, do not distract from the overall results.
Defibrillation threshold (DFT) testing was minimal and if
DFTs under 30 joules could not be obtained, the device was
still implanted. Also, the device was programmed as a “shock
only” device without any of the benefits of antitachycardia
pacing programmed “on.” Finally, the hazard ratio for those
patients with a left ventricular EF over 30% (285 patients)
was 1.08. The hazard ratio for patients with EFs equal to or
under 30% (1,390 patients) was 0.73. Thus, there was no
benefit of the ICD in patients with an EF between 30% and
35%. The benefit of ICD therapy was greater in patients with
a QRS duration of greater than or equal to 120 msec (hazard
ratio, 0.67). This finding was also noted in the MADIT II
trial. While there was a significant reduction in mortality
in patients with NYHA class II (7.9% at 5 years), patients
with NYHA class III HF had no apparent reduction in the
risk of death (hazard ratio of ICD vs placebo 1.16). Despite
these data, the authors state in the discussion that “we do
not believe that the unanticipated subgroup effect will be
found as a sufficient basis for withholding ICD therapy
from patients in NYHA class III.” This recommendation is
in conflict with the authors own data and is in contrast to
the findings of the MADIT II trial. Medicare has recently
agreed to fund the SCD-HeFT indications in broad decision,
which includes all patients with an EF <35% due to either
an ischemic or nonischemic cause and irrespective of
NYHA HF studies or QRS duration (CMS memo accessible
at http://www.cms.hhs.gov/mcd/viewdraftdecisionmemo.
asp?d = 139).
ICD Trials: The Future of a Mature Technology
Using data from the primary and secondary prevention
trials, an algorithm for treatment of most high-risk patient
groups encountered in clinical practice can be constructed.26
(Fig. 2) Patient groups not specifically studied in these trials
include patients with sustained VT due to coronary disease or
a DCM and an EF over 35%. We know that these patients do
well clinically and these might be groups in which electrophysiologic study is warranted to define antiarrhythmic drug
effect.
A 15-year era, between 1988 and 2003, of randomized
clinical trials of the ICD in high-risk patient groups is concluding. A few more select patient populations may be studied
in randomized trials in the future, such as patients with DCM
and syncope. Yet there are no other major patient populations
at high risk who are unstudied using current stratification
techniques. We need to develop better noninvasive tools—
perhaps including genetic and neurohumoral markers—to
identify the patient populations with low EF who may benefit from ICD; but to date this promise is unrealized. The
prophylactic ICD trials have all shown that mortality risk is
associated with a low EF (<40%) in CAD patients and that
other risk stratifiers including nonsustained VT, the signal
average ECG, and electrophysiological study add little.
A remaining clinical challenge is to assure that patients
who meet criteria for an ICD actually receive them. The uncompleted research challenge for the prevention of sudden
death is to identify and protect a large number of patients at
risk in the general population but who do not have any of the
well-studied risk factors of the 1980s.27
The ICD is now regarded as an everyday therapy for
large groups of patients in hospitals of every size around
the world. It will be the core therapy for groups of patients identified by new techniques as being at risk for sudden death and a component of any implantable device to
treat HF. The evolution and acceptance of the ICD over two
decades are comparable to that of the other building blocks of
clinical cardiology including pacing, interventional cardiology, and echocardiography. This therapy is unique, however,
in that its inventors—Mirowski and Mower—envisioned
its importance 10 years before the first device was implanted and 30 years before clinical trials established its
efficacy.28
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Vol. 16, No. 9, Supplement, September 2005
Acknowledgment: The editorial assistance of Janice Zemlicka is gratefully
acknowledged.
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