Pii: s0002-9149(98)01016-9

Potential Benefit of Biventricular Pacing
in Patients with Congestive Heart Failure
and Ventricular Tachyarrhythmia
Christoph Stellbrink, MD, Angelo Auricchio, MD, Bjo¨rn Diem, MD, Ole-Alexander Breithardt, MD, Michael Kloss, MD, Friedrich A. Scho¨ndube, MD, PhD, Helmut Klein, MD, Bruno J. Messmer, MD, and Peter Hanrath, MD Treatment of congestive heart failure (CHF) aims for
class I: 50.8 6 13.6 years, p <0.001 each) and mean
symptomatic relief and reduction of mortality both from
QRS duration was longer with advanced CHF (NYHA
sudden death and pump failure. The implantable car-
class III 127.8 6 30 msec; class II 119.4 6 27.7 msec;
dioverter defibrillator (ICD) is highly effective in the pre-
class 0 –I: 103.9 6 17.7 msec, p <0.001, analysis of
vention of sudden death, but no mortality benefit in
variance) as was the mean PR interval (NYHA class III
advanced CHF has yet been shown. Biventricular pacing
189.9 6 33.5 msec; class II 176.1 6 29.3 msec; class 0–I
may lead to functional improvement in selected patients
162.7 6 45.9 msec, p <0.001, analysis of variance). The
with CHF. Thus, a biventricular pacemaker with defibril-
incidence of atrial fibrillation was higher in class III (25.5%)
lation capabilities may be ideal for patients with ad-
compared with class 0–I (16.9%) and class II patients
vanced CHF. We retrospectively analyzed the data from
(14.1%, p 5 0.043, chi-square test). A total of 28 patients
384 patients (age 59 6 12 years, 322 male and 62
(7.3%) fulfilled eligibility criteria for biventricular pacing if
female) with regard to New York Heart Association
NYHA class III patients were considered candidates and 48
(NYHA) CHF class, mean QRS duration, mean PR inter-
val, presence of a QRS >120 msec and incidence of
(12.5%) if patients with NYHA II CHF and ejection fraction
<
atrial fibrillation at the time of ICD implantation. Based
30% were included. Thus, biventricular pacing may offer
on eligibility criteria from studies in biventricular pacing,
a promising therapeutic approach for a significant propor-
we analyzed how many patients may benefit from
tion of patients with CHF at risk for ventricular
biventricular pacing. Patients with CHF were older
tachyarrhythmia. Q1999 by Excerpta Medica, Inc.
(NYHA class III: 60.9 6 9.7, class II: 61.3 6 10 versus
Am J Cardiol 1999;83:143D–150D
Congestive heart failure (CHF) is one of the major an ICD with left or biventricular pacing capabilities
healthcare problems in the world, afflicting 2– 4 may be an attractive therapy for patients with CHF at million people in the United States and nearly 15 risk for ventricular tachyarrhythmia. Therefore, we million people worldwide.1–3 The incidence of heart analyzed the number of patients with an ICD indica- failure is age dependent: 1–5 per 1,000 population tion who may be candidates for left or biventricular each year in the total population to as high as 30 – 40 pacing as an adjunct therapy for CHF.
per 1,000 population each year in people $75 years ofage.2,4 Thus, in an aging society, the prevalence of PATIENTS AND METHODS
heart failure is increasing despite a reduction in car- The databases of 2 university hospitals (University diovascular mortality: in the United States, there was of Aachen and University of Magdeburg, Germany) a net growth of the CHF population of 428,000 pa- were retrospectively analyzed with regard to the clin- tients in 1990.5 Mortality from CHF remains high: in ical and electrocardiographic parameters at the time of the Framingham study the 5-year survival rate from implantation in 384 consecutive patients who under- the time of diagnosis was ,40%. Sudden cardiac went ICD implantation at both institutions. There death—mostly caused by ventricular tachyarrhyth- were 322 men (84%) and 62 women (16%). The mean mia—is a major threat to CHF patients and can be age at implantation was 59 6 12 years. Underlying effectively prevented with the implantable cardio- heart disease was coronary artery disease in 264 verter defibrillator (ICD). However, medical treatment (68.8%), dilated cardiomyopathy in 71 (18.5%), idio- remains the most common therapeutic approach for pathic ventricular fibrillation in 20 (5.2%), arrhythmo- symptomatic relief. Recent data suggest that left or genic right ventricular dysplasia in 8 (2.1%), valvular biventricular pacing therapy may have the potential to heart disease in 11 (2.9%), and other in 10 patients improve the functional status of CHF patients. Thus, (2.6%). Mean left ventricular ejection fraction as de-termined 38.3 6 15.4%. Indication for ICD implantation was From the Department of Cardiology and Internal Medicine and the aborted sudden cardiac death in 135 (35.2%), recur- Department of Thoracic and Cardiovascular Surgery, University of rent sustained ventricular tachycardia in 162 (42.2%), Technology, Aachen, Germany; and Department of Cardiology and and both in 56 patients (14.6%). Recurrent syncope Internal Medicine, Otto Guericke Universita¨t, Magdeburg, Germany.
with inducible sustained ventricular tachycardia was Address for reprints: Christoph Stellbrink, MD, Medizinische Klinik present in 15 patients (3.9%) and nonsustained ven- I, Universita¨tsklinikum der RWTH Aachen, Pauwelsstr. 30, D-52072Aachen, Germany.
tricular tachycardia with inducible but nonsuppress- 1999 by Excerpta Medica, Inc.
All rights reserved.
TABLE I Inclusion and Exclusion Criteria of the Pacing Therapies for Congestive Heart
Failure (PATH-CHF) Trial
Inclusion Criteria Exclusion Criteria CHF NYHA functional class III–IV (.6 mo) Life expectancy ,6 mo Dilated cardiomyopathy (any etiology) QRS $120 msec ($2 leads) AF within the last 6 mo PR interval $150 ms History of sustained VT/VF* Ability to tolerate anesthesia/surgery Patient on optimal individual drug therapy Pacemaker indication Sinus rate .55 beats/min Angina pectoris CCS class III–IV Able to perform CPX testing Unexplained syncope* Concomitant cardiac surgery Renal insufficiency requiring hemodialysis MI within the last 3 months Patients dependent on IV inotropes Previous valve replacement or reconstruction* Severe aortic or mitral valve disease AF 5 atrial fibrillation; CCS 5 Canadian Cardiac Society; CHF 5 congestive heart failure; COPD 5 chronic obstructive pulmonary disease; CPX 5 cardiopulmonary exercise testing; FEV1 5 forced expiratory volume in 1second; HOCM 5 hypertrophic obstructive cardiomyopathy; ICD 5 implantable cardioverter defibrillator; IV 5intravenous; MI 5 myocardial infarction; NYHA 5 New York Heart Association; VF 5 ventricular fibrillation;VT 5 ventricular tachycardia.
*Not used for eligibility analysis.
ible sustained ventricular tachycardia in late postin- farction patients in 16 patients (4.2%). The incidence Table II summarizes the results for the patients in of symptomatic CHF (New York Heart Association the different functional stages of CHF. Both patient [NYHA] class $2) was 82% (315 patients). All pa- groups with CHF were significantly older than those tients were analyzed with regard to the presence of without functional limitation (p ,0.001 each com- clinical criteria making them potential candidates for pared with class 0 –I). The incidence of coronary ar- bi- or left ventricular pacing at the time of ICD im- tery disease was also significantly higher in patients plantation. The criteria were chosen based on the with CHF than in those without, although there was no inclusion criteria of the Pacing Therapies for Conges- difference between patients in NYHA class II or III. In tive Heart Failure (PATH-CHF) study6 (Table I).
contrast, there was a further increase in the percentage Some exclusion criteria were not used because they of patients with nonischemic cardiomyopathy when were not applicable to ICD patients or were specified class III patients were compared with those with only for some of the features of the PATH-CHF study mild heart failure. Not unexpectedly, left ventricular design. The same analysis was performed with inclu- ejection fraction was significantly lower with ad- sion of patients with NYHA class II heart failure, but vanced stages of CHF (p ,0.001 for each individualcomparison). Conversely, the incidence of patients with severely depressed left ventricular ejection frac- with a QRS .120 msec showed a significant increase tion (#30%). For group comparison, patients were from 9.7% in class 0 –I to 52.8% in class III (Figure stratified into 3 groups according to their functional 1). Of the patients with intraventricular conduction class of CHF at the time of implantation as judged by delay, a QRS width of .150 msec was present in 48 the implanting physician: patients with no signs of of all 129 patients with QRS prolongation (37%): 3 of CHF (NYHA class 0 –I), patients with mild CHF 7 patients in NYHA class 0 –I (43%), 26 of 66 in class (NYHA class II), and patients with moderate-to-se- II (39%), and 19 of 56 in class III (34%). The inci- vere heart failure (NYHA class III). All electrocardio- dence of atrial fibrillation was significantly higher in grams were reviewed by 2 independent observers.
patients of NYHA class III CHF compared with pa- Mean age, left ventricular ejection fraction, resting tients with no or mild heart failure (p ,0.05), but no heart rate, and PR and QRS interval were compared significant difference was observed between patients using analysis of variance. When significant differ- with class 0 –I or class II (Figure 1). Mean QRS duration ences were present, individual groups were compared and PR interval also significantly increased with ad- using a 2-tailed paired t test. Gender proportion, inci- vanced functional class of heart failure (Figure 2). In dence of coronary artery disease and dilated cardio- class III patients, mean heart rate at rest was significantly myopathy, incidence of atrial fibrillation, and a QRS higher compared with class II patients (p 5 0.006) and width of .120 msec were compared using a chi- patients in class 0 –I (p 5 0.01, Table II).
square test. Values of p ,0.05 were considered sta- The eligibility analysis for left or biventricular pacing is outlined in Figure 3. There were 106 patients 144D THE AMERICAN JOURNAL OF CARDIOLOGYT

TABLE II Presence of Electrocardiographic Abnormalities in Implantable Cardioverter Defibrillator Patients According to New York
Heart Association (NYHA) Class
Incidence of CAD (%) Incidence of DCM (%) Heart rate (beats/min 6 SD) Incidence of AF (%)‡ PR interval (ms 6 SD) QRS width (ms 6 SD) AF 5 atrial fibrillation; CAD 5 coronary artery disease; DCM 5 dilated cardiomyopathy; LVEF 5 left ventricular ejection fraction; NS 5 not significant; SD 5 standard deviation.
*By analysis of variance.
†Chi-square test.
‡Within the last 6 months before implant.
with NYHA class III heart failure. Of these, 56 had a vere chronic obstructive pulmonary disease that QRS of .120 msec in at least 2 surface electrocar- limited his cardiopulmonary performance and 1 pa- diographic leads. Two patients had to be excluded tient had a previous disabling stroke. Of the remaining because they were unable to perform significant exer- 52 patients, 8 were excluded because either they had a cise due to noncardiac reasons as assessed by cardio- recent myocardial infarction (n 5 3), or a surgical pulmonary exercise testing (1 patient after leg ampu- revascularization was planned in addition to ICD im- tation, 1 patient with coxarthrosis); 1 patient had se- plantation (n 5 5). These were excluded because FIGURE 1. Comparison of mean left ventricular ejection fraction, incidence of QRS prolongation
>120 msec, and atrial fibrillation between different stages of congestive heart failure
(n 5 384). Mean left ventricular ejection fraction (EF), incidence of QRS width >120 msec (in
>2 surface electrocardiographic leads) and incidence of atrial fibrillation (AF) in patients with
no or minimal (New York Heart Association [NYHA] 0 –I), mild-to-moderate (NYHA II), and
severe (NYHA III) heart failure are shown. Mean EF significantly decreased with advanced
stages of heart failure. Conversely, there was a significant increase in QRS duration. The AF
incidence was highest in NYHA III patients, whereas there was no significant difference be-
tween class 0 –I and class II. See text for statistical analysis.
A SYMPOSIUM: ELECTRICAL MANAGEMENT OF CARDIAC DISORDERS

FIGURE 2. Mean PR interval and QRS duration depending on the New York Heart Association
(NYHA) functional class (n 5 384). Mean PR interval and QRS width are shown for the differ-
ent stages of heart failure. Both PR interval and QRS width significantly increased with in-
creasing functional heart failure class. * Denotes the number of patients analyzed after exclu-
sion of patients with atrial fibrillation or permanent pacing in the ventricle. See text for statisti-
cal analysis.
some degree of functional improvement could be ex- of CHF14 (Table III). Ventricular tachyarrhythmia has pected due to resolving myocardial stunning after the been implicated as the underlying mechanism for sud- recent infarct or due to improvement of cardiac func- den death in ;80% of ambulatory patients in whom tion after restoration of blood supply by surgical re- Holter recordings could be obtained at the time of vascularization. Finally, 16 patients were excluded death.15–22 However, in patients with CHF the inci- because they had had atrial fibrillation within the last dence of bradyarrhythmia and electromechanical dis- 6 months (n 5 13), had a PR interval of ,150 msec sociation may be considerably higher.23 Nevertheless, (n 5 2), or had some indication of sinus node dys- ventricular arrhythmia is a frequent finding in patients function (n 5 1). Thus, 28 patients remained as can- with CHF, and nonsustained ventricular tachycardia didates for pacing therapy for CHF equaling 7.3% of observed on ambulatory Holter recordings has been the total ICD population or 26.4% of all patients in shown to be an independent predictor both of total NYHA class III. If patients with NYHA class II heart mortality9,24–26 and sudden cardiac death.27 failure and severely depressed left ventricular function Role of medical treatment: Apart from reduction of
were included, the number increased to 48 patients mortality, the second main goal of medical treatment (12.5% of the ICD population, Figure 3).
of CHF is functional improvement. Digitalis is com- monly prescribed in patients with CHF, and it has Mortality and sudden death in CHF: Mortality from
been shown that withdrawal of digoxin leads to wors- CHF is mainly caused by progressive pump failure ening of symptoms.28,29 However, there seems to be and sudden death and strongly depends on the func- no positive effect on mortality.30 Similarly, diuretics tional stage of CHF: patients with mild CHF, i.e., may play a role for symptomatic relief only.31 Angio- NYHA class II, have a 1-year mortality of 5–15%,7,8 tensin-converting enzyme inhibitors not only lead to which increases to 20 –50% in class III patients.9–11 In symptomatic improvement in patients with CHF but class IV patients, which make up approximately 10 – also decrease mortality, both in patients with left ven- 15% of the heart failure population, the outcome is tricular dysfunction and CHF 7,13 and in patients with least favorable, with a 1-year mortality exceeding postinfarction CHF.32–34 However, it is still unclear 50%.12,13 The proportion of sudden deaths in relation whether these agents also decrease the sudden cardiac to total mortality decreases with worsening symptoms death rate: in nonselected CHF populations, no signif- 146D THE AMERICAN JOURNAL OF CARDIOLOGYT

is general agreement that class I agents should not beused in CHF patients. In contrast, several studies fromthe prethrombolytic era have shown improved overallsurvival and a reduction of sudden death in postin-farction patients receiving b-blocker treatment.38–40In a recent survey of .200,000 patients with myocar-dial infarction, this beneficial effect was also presentin patients who received thrombolytic treatment; pa-tients with left ventricular dysfunction and symptomsof CHF had the same benefit from b-blocker treatmentas patients with well-preserved left ventricular func-tion.41 In fact, some data suggest that b-blocker treat-ment (if tolerated in the run-in phase) may decreasemortality in patients with mild-to-moderate heart fail-ure.42 However, few data are, as yet, available onpatients with severe CHF. Nevertheless, b blockersare being increasingly used as a therapeutic alternativein CHF. The class III agent amiodarone has failed toshow significant improvement in overall survival inhigh-risk postinfarction patients, despite a significantreduction of arrhythmic or sudden death.43,44 A sig-nificant mortality reduction was shown for a popula-tion of patients with predominantly nonischemicCHF,45 whereas there seems to be no significant re-duction of mortality in ischemic cardiomyopathy.46 Ina meta-analysis of 13 postinfarction and CHF trialswith amiodarone, a small, marginally significant re-duction of total mortality could be demonstrated.47However, the investigators stated that confirmation of FIGURE 3. Analysis of eligibility for pacing therapy in congestive
these results by a single, large-scale trial would be heart failure (CHF). This graph illustrates the eligibility analysis
desirable. Thus, it may be concluded that amiodarone process both for patients with New York Heart Association
can be safely administered to patients with CHF at risk (NYHA) class III CHF (left ) and after inclusion of patients with
for sustained ventricular tachyarrhythmia, although a NYHA class II CHF and a left ventricular ejection fraction (EF)
clear mortality benefit has not been demonstrated.
<30% (right ). Numbers above arrows refer to the patients ex-
Pooled data from several studies do not show a reduc- cluded for NYHA class III and NYHA class II—EF <30%.
AF
tion in mortality with the use of calcium antagonists in 5 atrial fibrillation; CABG 5 coronary artery bypass
surgery; COPD 5 chronic obstructive pulmonary disease; CPX 5
patients after myocardial infarction.48 There is, as yet, cardiopulmonary exercise test; MI 5 myocardial infarction;
only 1 randomized, prospective study that showed an SND 5 sinus node dysfunction.
improved outcome with the calcium antagonist amlo-dipine49 in patients with advanced CHF. Moreover,there seems to be some functional improvement with icant decrease of the sudden death incidence with diltiazem in idiopathic CHF.50 angiotensin-converting enzyme inhibitors was ob- Role of the ICD in CHF: The Antiarrhythmics Versus
served,7,13 whereas in trials including postinfarction Implantable Defibrillators (AVID) trial has shown im- patients who had left ventricular dysfunction with proved survival with the implantable defibrillator in predominantly mild CHF, the incidence of sudden patients who have either survived sudden cardiac death was significantly lower in the treated group.34,35 death or in patients with sustained, hemodynamically Class I antiarrhythmic agents have been shown to compromising ventricular tachycardia and decreased increase mortality after myocardial infarction,36 and in left ventricular function51; similar results have been patients with CHF and atrial fibrillation.37 Thus, there reported for the Canadian Implantable DefibrillatorStudy (CIDS)52 and Cardiac Arrest Study Hamburg(CASH)53 studies (publication of final results pend-ing). The Multicenter Automatic Defibrillator Implan- TABLE III Sudden Death Dependent on the Severity of
Congestive Heart Failure
tation Trial (MADIT)54 focused on primary preven-tion of sudden death in patients with decreased left ventricular function in the chronic state after myocar- dial infarction, nonsustained VT noted on Holter re- cording, and inducible but nonsuppressible VT during invasive electrophysiologic study. This study also showed a reduction of total mortality in patients NYHA 5 New York Heart Association.
treated with an ICD compared with medical treatment, Reproduced with permission from J Am Coll Cardiol.14 consisting mainly of amiodarone. However, total mor- A SYMPOSIUM: ELECTRICAL MANAGEMENT OF CARDIAC DISORDERS

FIGURE 4. Radiograph of biventricular ICD. Anteroposterior view of a pectorally implanted ICD
in a patient with ventricular tachyarrhythmia, congestive heart failure, and a widened QRS
complex. The defibrillation lead and the atrial lead are placed conventionally via the left sub-
clavian vein in the right ventricle and atrium, respectively. An additional bipolar lead is placed
epicardially via a small lateral thoracotomy on the left ventricular free wall. The atrial lead is
used for triggering of biventricular pacing to optimize atrioventricular delay (VDD mode).
ICD 5 implantable cardioverter defibrillator; LV 5 left ventricle; RV 5 right ventricle;
SVC 5 superior vena cava.
tality remains high in patients with CHF and an im- late into chronic functional improvement is currently planted ICD.55 Moreover, in a nonrandomized study being investigated in several studies, such as the by Sweeney et al,56 the ICD did not improve survival PATH-CHF,6 the Vigor-CHF,69 and the Multisite in patients with endstage CHF awaiting heart trans- Stimulation in Cardiomyopathy (MUSTIC) trial.70 plantation despite a reduction of sudden death. Thus, Notably, Saxon et al69 demonstrated a reduction of the concern remains that, in patients with advanced plasma norepinephrine levels in CHF patients with CHF, conventional ICD treatment may simply convert biventricular pacing, a finding that may have impor- the mode of death from arrhythmic death to pump tant prognostic implications in this subset of patients, if it can be confirmed in larger studies. A recent Pacing for CHF: There are few data available on the
analysis in a CHF clinic population estimated that effect of pacing therapy on cardiac pump function.
about 6% of all CHF patients fulfill the eligibility Hochleitner et al59 showed substantial functional im- criteria of the PATH-CHF study and may, therefore, provement in patients with CHF treated with conven- potentially benefit from this therapeutic approach,71 a tional dual-chamber pacing (using right ventricular proportion of patients that would increase to 13% if apical pacing). In an acute study, Auricchio et al60 patients with atrial fibrillation could be included and demonstrated hemodynamic improvement in CHF pa- the pacemaker had defibrillation capabilities.
tients when the atrioventricular delay was optimized, Potential for a biventricular ICD: Figure 4 shows a
2 other studies found similar results.61,62 However, radiographic image of an implanted ICD with addi- these data were challenged by other investigators who tional left ventricular pacing leads for optimization of did not observe any significant improvement.63–65 left ventricular function in a patient with advanced More recently, interest in pacing for CHF was re- CHF and a prolonged QRS complex. Based on the newed by the idea that optimization of atrioventricular available data on the potential benefit that left or delay, as well as resynchronization of ventricular ac- biventricular pacing may offer for CHF patients, it tivation, may exert positive hemodynamic effects.
may be speculated that such a combined device may This may be accomplished by finding the optimal not only lead to a dramatic reduction in sudden death pacing site(s) in the right or left ventricle. Both bi- and but, due to functional improvement in a significant left ventricular pacing have shown acute hemody- number of patients with CHF, also decrease the po- namic improvement in patients with a widened QRS tential of conversion of the mode of death from sud- complex at baseline.6,66–68 Whether these data trans- den to pump failure death. Thus, with additional he- 148D THE AMERICAN JOURNAL OF CARDIOLOGYT
modynamic support, the ICD may eventually become minor. In addition, ICD treatment seems to be more an effective bridge to heart transplantation in patients effective for primary prevention of sudden death in with end-stage CHF. Moreover, a biventricular ICD some high-risk subgroups. However, CHF remains the may offer a new, effective therapy for the desperate leading cause of death in patients with an implanted patient with NYHA class IV CHF who is not a can- ICD. Thus, there is great need for optimized care for didate for transplantation and who is generally not pump failure to prevent functional deterioration in considered an ICD candidate because of his or her ICD patients with CHF. Biventricular or left ventric- extremely poor prognosis due to potential death from ular pacing with optimized atrioventricular delay is a pump failure. It seems reasonable to assume that a new treatment modality that may improve functional proportion of NYHA class IV patients may fulfill the capacity and, thus, quality of life in a subgroup of eligibility criteria comparable to the 26% of class III CHF patients with intraventricular conduction delay.
patients in our series (most likely, there will be more It may be speculated that pacing for heart failure patients with QRS prolongation, but on the other hand, combined with antitachycardia options may decrease more patients with atrial fibrillation). Thus, there may mortality in these patients with moderate-to-severe be a significant number of class IV patients who may CHF. Future studies will address the use of pacing in benefit from additional pacing therapy for CHF. Pa- patients with mild-to-moderate (NYHA class II) or tients with severely depressed left ventricular function more advanced (NYHA class IV) heart failure and and yet only mild symptoms of CHF are currently atrial fibrillation and may renew interest in the use of being investigated in 2 trials: the Ventak-CHF trial in the ICD as an electronic bridge to transplant.
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150D THE AMERICAN JOURNAL OF CARDIOLOGYT

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