an ICD in All Patients With Heart Failure?
D.S. C
ANNOMRecent clinical trials of implantable cardioverter defibrillators (ICD) suggest that up to 50% of the deaths in patients with left ventricular systolic dys- function (LVSD) secondary to coronary artery disease (CAD) are sudden or arrhythmic in nature [1]. This incidence is lower in heart failure (HF) due to non-ischaemic aetiologies. 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 β-blockers, New York Heart Association (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 [2].
Attempts at identifying which patients with HF are at an increased risk of sudden cardiac death (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 [3–5]. High-fre- quency 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 [6, 7]. Inducibility of ventricular tachycardia (VT)/ventricular fibrillation (VF) during electrophysiology testing (EPS) has a low sensitivity in patients with non-ischaemic or dilated cardiomyopathy (DCM). It does predict an increased risk of SCD in ischaemic cardiomyopa- thy (CM), but does not predict overall mortality [8, 9].
Good Samaritan Hospital, Los Angeles, CA, USA
The results of the recently completed ICD trials – including Multicenter Automatic Defibrillator Implantation Trial (MADIT) I and II, Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE), Sudden Cardiac Death in Heart Failure (SCD-HeFT) and Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) – clearly establish a survival advantage for selected patients with HF who receive an ICD. The largest HF trial is COMPANION, which enrolled patients based on both advanced HF status (NYHA class III and IV) and a low EF: both a sur- vival benefit and reduced congestive heart failure (CHF) hospitalisation for cardiac resynchronisation therapy (CRT) and ICD therapy in combination was clearly seen. In less advanced heart failure (NYHA class I and II), the most important risk stratifier seems to be ejection fraction rather than CHF status (see below).
The Role of the ICD in Preventing SCD in Patients with CAD
Three well-designed primary prevention trials in patients with reduced EF and CAD support a role for the ICD in patients with low EF [10–12]. MADIT I and the Multicenter Unsustained Tachycardia Trial (MUSTT) examined patients with CAD, EF below 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 (approx. 40% of patients), EF below 26%, or left bundle branch block (LBBB) [10]. MUSTT showed a 27% risk reduction in SCD sole- ly attributed to use of the ICD and not anti-arrhythmic drug therapy [11].
Approximately two-thirds of the enrolled patients were either NYHA class II or III. MADIT II evaluated patients with CAD and EF below 30% and did not require inducibility of VT/VF by EPS. The ICD produced a 31% risk reduc- tion in overall mortality, with the majority of the benefit occurring in patients with a QRS duration greater than 120 ms [12]. Approximately 60%
of the patients were either NYHA class II or III.
The DEFINITE and SCD-HeFT Trials
Previous small studies examining the role of prophylactic ICDs among
patients with DCM did not define the role of the ICD. The Amiodarone ver-
sus Cardioverter Study (AMIOVIRT) reported no mortality difference
among patients with DCM and asymptomatic non-sustained ventricular
tachycardia (NSVT) [13]. 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 enrolment [14].
The neutral results of these studies were due to inadequacy of the sample size and the absence of a requirement for symptomatic heart failure, which in turn contributed to lower than expected event rates. In contrast, the recently reported Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial, which randomised 458 patients with DCM, left ventricular ejection fraction below 35%, and asymptomatic NSVT to receive ICD or conventional medical therapy, demonstrated a 34% reduction in all- cause mortality in ICD patients, but that did not reach statistical significance [15]. A post-hoc analysis of NYHA class III patients showed a 67% relative reduction in all-cause mortality, again showing that patients with left ven- tricular dysfunction and more advanced HF symptoms are most likely to benefit from ICD therapy, as in MADIT I and COMPANION.
The hypothesis of SCD-HeFT was to determine, by intention-to-treat analysis, whether either ICD or amiodarone reduces all-cause mortality com- pared with placebo in patients with ischaemic or dilated cardiomyopathy, NYHA class II–III HF and left ventricular ejection fraction of 35% or less [16]. Event estimates were based on an estimated 10% per year all-cause mortality rate in the control arm at a minimum follow-up of 2.5 years. A total of 2521 patients were enrolled between 16 September 1997 and 18 July 2001 at 148 sites in North America and New Zealand. Follow-up terminated on 31 October 2003 yielding a median (25th, 75th percentile) follow-up dura- tion of 40.8 (29.7, 53.0) months. This long follow-up duration exceeds that of any prior study of ICDs or drug therapy for prevention of SCD.
Fifty-two percent of enrolled patients had an ischaemic 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 earlier ICD trials. At last follow-up, 87% of patients were taking either an ACE or angiotensin receptor blockade (ARB), 78% were taking β-blockers, 80% were taking diuretics, and 31% were taking spironolactone. There were no important differences in relation to baseline demographic variables, substrate, NYHA class, or medical therapy among treatment groups, with the exception of slightly more β-blocker use in class II (71%) than in class III (64%) patients.
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 enrolment 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 ischaemic 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 demonstrates that the primary prevention mortality ben- efits of ICD therapy seen in ischaemic cardiomyopathy are identical to those seen in DCM populations.
There were many peculiarities in the SCD trial design but, although pre-
sent, they do not distract from the overall results. Defibrillation threshold
testing (DFT) testing was minimal, and if DFTs under 30 J 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 anti-tachycardia pacing
programmed ‘on.’ Finally, the hazard ratio for those patients with a left ven-
tricular ejection fraction over 30% (285 patients) was 1.08. The hazard ratio
for patients with ejection fractions equal to or under 30% (1390 patients)
was 0.73. Thus, there was no benefit of the ICD in patients with an ejection
fraction between 30% and 35%. The benefit of ICD therapy was greater in
patients with a QRS duration greater than or equal to 120 ms (hazard ratio
0.67). This finding was also noted in the MADIT II trial. While there was a
Fig. 1.The Kaplan–Meier estimates of death from any cause in the SCD-HeFT trial. Note the 5-year reduction in mortality by the ICD of 23% compared to either placebo or amio- darone. This difference was noted irrespective of the cause of the cardiomyopathy (ischaemic or dilated) but was limited to NYHA class II patients only. CI confidence intervalsignificant reduction in mortality in patients with NYHA class II disease (7.9% at 5 years), patients with NYHA class III CHF had no apparent reduc- tion in the risk of death (hazard ratio of ICD vs placebo 1.16) (Fig. 2).
Fig. 2a, b.The Kaplan–Meier estimates of death from any cause for the prespecified sub- groups of NYHA class II (a) and class III (b) in the SCD-HeFT trial. There was no apparent risk reduction of death in ICD therapy in class III patients compared with placebo (HR 1.16)
a
b
Despite this finding, 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.’ Recently presented data from SCD-HeFT showed that in surviving patients NYHA class actually improved over time for the surviving population within each treatment group [17]. This occurred despite the associated mortality in each arm. One possible explanation for this finding is that more intense pharma- cological therapy improved these patients and that their actual CHF status was misclassified at enrolment due to under-treatment with CHF medica- tion. An opposite finding was noted in MADIT II patients, 30% of whom had progression of their CHF over time: the role of right ventricular pacing is being evaluated as a possible cause of this deterioration.
Heart failure is probably not as relevant a way to select patients as the presence of a low ejection fraction alone. Of course most of these low ejec- tion fraction patients will have HF. But the inconsistency of benefit from the ICD across studies (e.g. the differences in benefit in class III patients between DEFINITE and SCD-HeFT) reinforces the importance of a low ejec- tion fraction rather than an attempt to categorise HF which depends upon a subjective interpretation of patient symptoms. Other causes of HF, e.g. dias- tolic dysfunction and a high ejection fraction, would not qualify a patient for an ICD. Medicare has recently agreed to fund the SCD-HeFT indications in a broad decision which includes all patients with an ejection fraction below 35% due to either an ischaemic or a non-ischaemic cause and irrespective of NYHA HF studies or QRS duration (Centers for Medicare and Medicaid Services memo accessible at http://www.cms.hhs.gov/mcd/viewdraftdeci- sionmemo.asp?d=139).
The COMPANION Trial
The COMPANION trial expanded the earlier studies of CRT that analysed only functional endpoints. These earlier trials, including those with an ICD, were intended primarily for US Food and Drug Administration approval for a specific device. However, the COMPANION trial was a serious scientific trial designed by some of the top experts in the HF and ICD world. Its design features and endpoints were chosen to clarify whether CRT alone or in com- bination with an ICD will improve mortality and morbidity in HF patients.
The COMPANION enrolment criteria included patients in NYHA class III
or IV HF, with normal sinus rhythm, QRS duration 120 ms or more, a PR
interval of 150 ms or more, left ventricular ejection fraction 35% or less, and
left ventricular end-diastolic dimension 60 mm or more [18]. Enrolled
patients were required to be taking optimal pharmacological therapy (OPT)
including a β-blocker for at least 3 months, a diuretic, ACE inhibitor or ARB, and spironolactone for 1 month. Furthermore, patients had to have a history of a hospitalisation for HF in the year before enrolment. Patients were ran- domised in a 1:2:2 strategy to OPT alone, OPT with CRT, or OPT with CRT-D (CRT + ICD). The primary endpoint of the trial was the time to all-cause mortality or all-cause hospitalisation. A secondary endpoint was all-cause mortality.
The first patient was enrolled in the trial on 20 January 2000. On 18 November 2002, the Data and Safety Monitoring Board recommended that the Steering Committee stop enrolment because a target number of primary endpoints had been reached, and the primary endpoint and efficacy bound- aries had been crossed. Therefore, enrolment was stopped on this date.
The randomisation was very consistent across all three groups. More than 80% of the patients were in NYHA class III rather than class IV HF. Also, the mean ejection fraction of the enrolled population was between 20% and 22%, which is only slightly lower than that of MADIT II (which was 23%).
QRS duration averaged 158–160 ms, with approximately 70% of the patients having LBBB rather than right bundle branch block (RBBB). Despite the fact that the use of β-blockers and ACE inhibitors was required for enrolment, only 70% of the population was on ACE inhibitors, and 66–68% were on β-blockers at the time of randomisation. This demonstrates the difficulty in maintaining patients on these drugs even in a carefully controlled research environment.
The main reason that the primary endpoint of the COMPANION trial was met was the very high event rate (68%) in the OPT group. Both CRT and CRT-D reduced the primary endpoint (hospitalisation for CHF or death) by 20% (P = 0.008 for CRT and 0.007 for CRT-D). Although only 1600 patients were enrolled, the high event rate in the OPT group allowed the primary endpoint to be successfully reached.
The endpoint of greatest interest to the electrophysiology community was the effect of CRT-D on the secondary endpoint of all-cause mortality. The 12- month mortality in the OPT group was 19% and was double that at 24 months. CRT alone reduced 1-year mortality by 24% (P = 0.06), and CRT-D reduced the 1-year mortality by 43% (P = 0.003) compared to OPT (Fig. 3).
It is important for the clinician to appreciate that only 54–59% of the patients in this trial (depending on which arm is being considered) had an ischaemic cardiomyopathy. It also appears that the CRT benefit was equal for NYHA class III and class IV patients. QRS width affected survival, with the greatest benefit for those patients with the widest QRS (locker use was asso- ciated with a significantly more favourable outcome.
On the basis of these data, there is now scientific evidence to support the
concept that CRT-D reduces HF mortality. The COMPANION trial showed
that two-thirds of this effect can be attributed to CRT alone, whereas one- third is attributable to the ICD. Thus, all patients considered for CRT in 2005 are candidates for a back-up ICD as well.
Conclusions
Few, if any, technological breakthroughs in clinical electrophysiology have reached broad acceptance as quickly as the ICD and CRT. The impact of these devices on patients with end-stage HF has been an important clinical adjunct to routine background medical therapy. This field has changed so rapidly that the clinician still wrestles with the problems of how far to extend prophylactic ICD therapy to the HF population and which patients should be selected for CRT therapy and, in turn, for CRT-D therapy. A North American Society of Pacing and Electrophysiology (NASPE) Consensus Conference on Resynchronization Therapy for Heart Failure held in 2002 noted that although much progress has been made, there are many issues that still must be resolved [19]. These include the long-term benefit of device therapy, the need for further evolution of the devices themselves to assure successful implantation, studies to help optimise programmability, identifi- cation of the patient population most likely to benefit, and the importance of the economic and ethical ramifications.
Fig. 3.The Kaplan–Meier estimates of the time to the secondary endpoint of death from any cause in the COMPANION trial. The 12-month rates of death from any cause (the secondary endpoint) were 19% in the pharmacological-therapy group, 15% in the pace- maker group, and 12% in the pacemaker–defibrillator group
One of the major challenges for the next few years is to ascertain whether we can extend the indications for CRT by implanting these devices in patients with CAD, a low ejection fraction (in the 30% range), a wide QRS (> 120 ms), and in NYHA class I or II. Such a study is MADIT CRT, which will test the hypothesis that these high-risk patients who receive CRT will subsequent- ly have a reduced rate of HF or all-cause mortality. This important protocol was initiated in October 2004 and will enrol 1700 patients over 2 years. A similar study called Biventricular Pacing to Inhibit HF Progression (BLOCK- HF) will evaluate the potential benefit of CRT on HF progression. There are important design differences between MADIT CRT and BLOCK-HF, although both seek to answer the question as to whether CRT benefits patients before they progress to NYHA class III or IV HF. Trials such as these will further enhance our knowledge and ability to treat SCD in HF.
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Available at: http://www.hrsonline.org/professional_education_categories/articles (accessed 19 January 2005)
