- Email: [email protected]
The pacing therapies for congestive heart failure (PATH-CHF) study: rationale, design, and endpoints of a prospective randomized multicenter study1
The Pacing Therapies for Congestive Heart Failure (PATH-CHF) Study: Rationale, Design, and Endpoints of a Prospective Randomized Multicenter Study Angelo Auricchio, MD, PhD, Christoph Stellbrink, MD, Stefan Sack, MD, Michael Block, MD, Ju¨rgen Vogt, MD, Patricia Bakker, MD, Peter Mortensen, MD, and Helmut Klein, MD, for the PATH-CHF Study Group In conjunction with pharmacologic therapy, pacing has been proposed as a potential treatment to decrease symptoms in patients with moderate-to-severe congestive heart failure (CHF). Uncontrolled studies of pacing therapy for CHF dealing with different pacing sites, modes of pacing, and atrioventricular delays have reported mixed outcomes. The Pacing Therapies in Congestive Heart Failure (PATH-CHF) study is a single-blind, randomized, crossover, controlled trial designed to evaluate the effects of pacing on acute hemodynamic function and to assess chronic clinical benefit in patients with moderate-to-severe CHF. The effect of pacing on oxygen consumption at peak exercise and at anaerobic threshold during cardiopulmonary exercise tests, and on 6-minute walk distance, have been selected as primary endpoints of the study. Secondary endpoints of the trial were changes in New York Heart Association (NYHA) functional class, quality-of-life as assessed by the Minnesota Living with Heart Failure questionnaire, and hospitalization frequency. Finally, changes in ejection fraction, cardiac output, and filling pattern were assessed by
echocardiography. The trial was planned to include 53 patients from 7 centers in Europe over a period of 3 years. The study was divided into 2 parts: acute testing and chronic follow-up. The acute study, performed during the pacemaker implantation, involved extensive testing using a custom-designed computer (FLEXSTIM) and a unique burst pacing protocol (FLEXSTIM protocol) to determine the best ventricular pacing sites and the most appropriate atrioventricular delays. The chronic phase consisted of a crossover study designed to test in each patient the best univentricular pacing site and biventricular pacing as assessed by the acute hemodynamic study. The study started with the first implant in 1995 and has, to date, included 42 patients. The study is expected to be completed by the end of 1998. The results of a first interim analysis showed trends toward improvement in all primary and secondary endpoints during the pacing periods compared with no pacing. Q1999 by Excerpta Medica, Inc. Am J Cardiol 1999;83:130D–135D
acing has been proposed as an adjunct therapy for treatment of symptoms in patients with moderateP to-severe congestive heart failure (CHF). Although
several small studies suggest that the electrical resynchronization of both ventricles, the septum, and the atria may be beneficial in the treatment of CHF patients who continue to deteriorate despite aggressive pharmacologic therapy.2 Although contradictory results have been reported with conventional atrial sequential right ventricular pacing,3,4 more consistent and positive data have been presented when pacing either in the left ventricle or in both ventricles.5,6 Many questions remain concerning the possible use of pacing for the treatment of CHF. Although some patients have benefited from pacing with shortened atrioventricular delays, others have not. This indicates that we do not yet understand the mechanisms involved, the interactions between the pacing site and the applied atrioventricular delay and the patient’s individual characteristics. Past clinical observations provide the rationale for prospective randomized testing of the effect of pacing therapy in CHF. We tested the hypothesis that in patients with moderate-to-severe heart failure and conduction abnormalities, left ventricular or biventricular pacing, at optimum atrioventricular delay, can improve symptoms and can be quantified by objective measures.
the initial report by Hochleitner et al1 could not be confirmed by other investigators, it suggested, for the first time, that electrical stimulation therapy might improve cardiac function. Currently, there is evidence that atrial sequential pacing either in the left or in both ventricles corrects electrical abnormalities and provides symptomatic relief to patients. The results of From the Department of Cardiology, University Hospital, Magdeburg, Germany; Department of Cardiology, University Hospital RWTH, Aachen, Germany; Department of Cardiology, University Hospital, Mu¨nster, Germany; Department of Cardiology, University Hospital, Essen, Germany; Heart Center, Bad Oeynhausen, Germany; University Hospital, Department of Cardiac Surgery, Utrecht, the Netherlands; Department of Cardiology, University Hospital, Aarhus, Denmark. For a complete list of institutions and individuals participating in the PATH-CHF Study Group, see the Appendix. Supported by a grant from Guidant Corporation-Cardiac Rhythm Management, St. Paul, Minnesota. Address for reprints: Angelo Auricchio, MD, PhD, Department of Cardiology, University Hospital, Leipzigerstr. 44, 39120 Magdeburg, Germany.
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©1999 by Excerpta Medica, Inc. All rights reserved.
0002-9149/99/$20.00 PII S0002-9149(99)01014-5
FIGURE 1. Design of Pacing Therapies in Congestive Heart Failure (PATH-CHF) study. After implantation, each patient was randomly assigned to either univentricular or biventricular pacing for 4 weeks followed by 4 weeks of no pacing and then 4 weeks of pacing in the second mode. At the end of 12 weeks, each patient was followed every other month for up to 1 year.
OVERVIEW OF THE STUDY DESIGN The design of the Pacing Therapies in Congestive Heart Failure (PATH-CHF) study is shown in Figure 1. The study consisted of 4 phases: (1) an evaluation phase before implant; (2) an acute testing phase using the FLEXSTIM during the implantation procedure; (3) a randomized crossover protocol that tests 2 different pacing modes with a no pacing (washout) period in between; and (4) a chronic pacing phase. Preimplant evaluation: The preoperative measurements included a review of medical history, physical examination, biochemical testing, chest x-ray, resting electrocardiogram, 24-hour Holter monitoring, echocardiogram, 6-minute walk exercise test, and completion of a quality-of-life questionnaire (“Living with Heart Failure” Questionnaire, University of Minnesota). The frequency and duration of previous hospital admissions due to cardiac events were recorded. In addition, patient activity was recorded using 2 surface accelerometers taped to the skin at the left pectoral and apical site. A right and left cardiac catheterization was performed in all patients to exclude possible organic heart disease amenable to cardiac surgery or to percutaneous coronary angioplasty. Intraoperative phase: At the time of the pacemaker implantation all patients underwent an acute testing using the FLEXSTIM (Guidant CRM, St. Paul, MN) computer. The main objective of the intraoperative testing was to guide the selection of the optimal atrioventricular delay and pacing site for the chronic phase. The procedure was performed while the patients were under general anesthesia. Chronic pacing leads were implanted as described below (see Implant Options). After femoral arterial and venous puncture using the Seldinger technique, patients were instrumented with two 8Fr dual micromanometer catheters (Model SPC780c; Millar Instruments, Houston, TX) in both sides of
the heart to provide right atrial, right ventricular, aortic, and left ventricular pressures. Pressure catheters and pacing leads were connected to the FLEXSTIM computer, which was designed to execute a randomized pacing protocol, acquire hemodynamic signals, and provide offline comparative analysis of the hemodynamic parameters collected during the pacing interventions. The rationale for the FLEXSTIM protocol was to measure the cardiac response to pacing. In fact, a controlled study to determine the effect of pacing chamber and atrioventricular delay is technically difficult because of the large number of possible pacing combinations. The analysis of the acute hemodynamic effects of pacing using the standard methodology (e.g., cardiac output determined by thermodilution7 or by Doppler examination8) is time consuming and may not provide sufficient data for meaningful statistical comparisons of the different pacing sites and atrioventricular delays in a single patient. Group statistics will be misleading when there are large interactions between individuals and pacing variables.9 In addition, normal physiologic changes in baseline during the study period must be taken into account.10 The FLEXSTIM protocol consists of periods of pacing in biventricular pacing (VDD) mode (i.e., atrial sensing followed by ventricular pacing, after an atrioventricular delay) separated by periods of no pacing in normal sinus rhythm in a 5 paced beat/15 nonpaced beat duty cycle (Figure 2). When pacing and no pacing sequences were interrupted by a premature ventricular contraction, additional beats were added to allow the premature ventricular contraction beat and surrounding beats to be removed from the analysis. Pacing was performed in the right ventricle, left ventricle, or right and left ventricles (biventricular 5 BV) simultaneously, at 5 different atrioventricular delays. The 5 atrioventricular delays were equally distributed
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FIGURE 2. Schematic representation of the FLEXSTIM computer and accessories (upper panel ) and pacing protocol used to test multiple combinations of pacing site and atrioventricular (AV) delay treatment combinations (lower panel ). The average of 6 baseline beats is represented by B and each paced beat is shown as Pn, where n can be 2, 3, 4, or 5. BiV 5 biventricular; LV 5 left ventricular; RV 5 right ventricular.
between 0 msec to 30 msec less than the patient’s intrinsic PR interval as measured by the intracardiac electrograms. Each treatment combination of pacing chamber and atrioventricular delay was repeated 5 times in random order for each patient. The entire sequence summed to 1,500 beats, which, at an average heart rate of 75 beats/min, required 20 minutes. Raw data were recorded on a 14-bit TEAC digital tape recorder (Model RD-130TE; TEAC America, Montebello, CA ) with sampling at 12,000 Hz and then down-sampled to 500 Hz for detailed offline analysis. Several hemodynamic parameters were automatically measured with custom signal analysis software (Guidant CRM). To compare pacing chambers and atrioventricular delays, an offline analysis of aortic diastolic pressure, aortic systolic pressure, pulse pressure, and left ventricular peak positive dP/dt (left ventricle 1dP/dt) was used. Implant options: To evaluate the relative chronic benefits of right or left ventricular, and biventricular pacing, we implanted standard right atrial and right ventricular endocardial pacing leads together with an 132D THE AMERICAN JOURNAL OF CARDIOLOGYT
epicardial pacing lead, positioned on the surface of the left ventricle. Currently, none of the pacemakers available can sense in the atrium and simultaneously pace both ventricles while maintaining flexibility to independently program atrioventricular delay and ventricular site (right or left ventricular or biventricular). Consequently, we considered a few implant options to pace both ventricles. The so-called split cathode requires the connection of a Y adapter to the pacemaker header to split the unipolar cathodal electrode into 2 arms. The right and left ventricles would be stimulated in parallel, but this would not give the option to switch between single chamber and biventricular pacing. On the other hand, the extended bipole or the connection of a bipolar Y adapter connected to the pacemaker header retains the capability to switch between single chamber and biventricular pacing by programming the pulse generator from unipolar to bipolar. Although chronic testing of all modes (right or left ventricular, or biventricular pacing) would not be possible, a comparison of biventricular pacing versus either one of the single chambers could be achieved. However, some
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FIGURE 3. Chest x-ray of a patient enrolled into the Pacing Therapies in Congestive Heart Failure (PATH-CHF) study. Pacemaker implanted in the right pectoral position (Vigor 1) was connected to a right atrial lead (RA 1) and to an endocardial right ventricular lead (RV endo). The pacemaker placed in the left pectoral position (Vigor 2) was connected to a second right atrial lead (RA 2) and to an epicardial screw-in lead (LV epi).
clinical data indicated increases in pacing threshold using this pacing modality with a high probability of losing capture in the anodal polarity of the bipole. Therefore, the only remaining possibility for implementing biventricular pacing with currently available hardware required implantation of 2 pulse generators, each one being connected to a right atrial lead and to a ventricular lead. Univentricular pacing could be obtained by setting the ventricular channel of 1 pulse generator to pace in unipolar (VDD) mode and the ventricular channel of the second pulse generator to pace in bipolar mode. Due to the fact that all the ventricular leads were unipolar, programming 1 pulse generator ventricular output to bipolar results in no output from the ventricular lead. Biventricular pacing could be initiated by setting 1 pulse generator to VDD mode while the other was programmed in VVT mode. Voltage outputs for each pulse generator could be adjusted according to each individual lead. All patients were implanted with 2 DDDR pacemakers (Vigor DDDR or Discovery DDDR; Guidant CRM). The first pacemaker was implanted and connected to a right atrial bipolar lead (Sweet-Tip, Guidant) and to a unipolar right ventricular lead (Sweet-Tip, Guidant). The second pacemaker was implanted and connected to a second bipolar right atrial lead and a unipolar left ventricular epicardial lead (Model 4316, Guidant or Model 4965, Medtronic, Minneapolis, MN) (Figure 3). For the duration of the study 4 different settings were allowed. A sequential
right atrium– univentricular pacing (right or left ventricle) was achieved by programming the first pacemaker in DDD mode and the second pacemaker in VVI mode at 30 beats/min with bipolar ventricular output. The lower rate limit of the DDD pacemaker was set at 40 beats/min to ensure back-up pacing, and the atrioventricular delay was set according to the results of the intraoperative testing. Atrial sequential biventricular pacing was obtained by programming 1 pacemaker in DDD mode (same setting as described above) and the second pacemaker in VVT mode. When no pacing therapy was desired, 1 pacemaker was programmed to VVI at 30 beats/min with bipolar ventricular output and the second pacemaker to VVI at 40 beats/min with unipolar ventricular output. The unipolar ventricular output setting with a low lower rate limit in 1 pacemaker allowed back-up pacing if required. Study procedures: At the time of discharge from the hospital, each patient proceeded into a randomized (1 : 1 ratio) chronic crossover study that involved testing of 2 pacing modes versus no pacing over a period of 12 weeks (Figure 1). The randomization procedure included 2 arms, one beginning with sequential atriouniventricular (right or left ventricle whichever was best, according to the acute study) pacing and the second one beginning with sequential atrio-biventricular (simultaneous right and left ventricular) pacing. After 4 weeks of pacing (week 0 – 4 of treatment), the pacemakers were programmed to no pacing for the next 4 weeks (week 4 – 8 of treatment) in all patients.
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After 4 weeks of no pacing, the patients were again paced over a period of 4 weeks (week 8 –12 of treatment). The programmed mode was then sequential atrio-biventricular if the patient was initially assigned to sequential atrio-univentricular pacing during the first 4 weeks of treatment, and vice-versa for the other arm of randomization. Early termination of each 4-week period of treatment could occur if the patient’s condition met the specified guidelines for crossing over to the next pacing mode. Although the study was completed after 12 weeks, all patients were followed clinically on a bimonthly basis up to 1 year after the implantation. Before reprogramming to another pacing mode (termination of each 4 weeks of treatment or clinically indicated early termination of the treatment period), all patients underwent a clinical examination, chest x-rays, and blood examination. In addition, a symptom-limited cardiopulmonary exercise test, a 6-minute walk test, ambulatory electrocardiographic monitoring, a quality-of-life questionnaire (Minnesota Living with Heart Failure Questionnaire), and an echocardiography examination were performed. Guidelines for crossover to the next mode: We recognized that complications or problems might occur that could affect the study protocol. In general, a patient had to complete the designated duration of each pacing mode before crossing over to the next mode. If there were atrial sensing problems or lead dislodgment that prevented consistent VDD pacing, we attempted to troubleshoot and correct the sensing problem by eventually repositioning the lead. If atrial sensing could be reinstated to permit consistent VDD pacing, the current pacing mode was restarted. If atrial sensing could not be reinstated, the patient was excluded from further participation in the study. The patients could also refuse a crossover or demand to be returned to a previous mode if they could discern a difference in symptoms from one pacing mode to the next. In such cases, the patient was programmed to the requested mode and was removed from the crossover portion of the study. However, the investigator continued to follow the patient on a bimonthly basis to evaluate the long-term effects of pacing therapy. Finally, if the patient’s condition worsened during any mode in the chronic phase, the investigator made every effort to treat the patient medically according to standard medical practice without disrupting the protocol. However, if the patient’s condition worsened significantly and hospitalization was required, the patient could be withdrawn from the current pacing mode, treated until stable, and eventually advanced to the next portion of the protocol.
PATIENT SELECTION All patients enrolled in the study had symptoms of moderate-to-severe heart failure with New York Heart Association (NYHA) classification of III (for at least 6 months) or IV, despite treatment at the maximum tolerated dosage with diuretics, angiotensin-converting enzyme inhibitors, digitalis, vasodilators or nitrates, and b blockers. The complete list of inclusion and exclusion criteria can be found in Table I. The 134D THE AMERICAN JOURNAL OF CARDIOLOGYT
TABLE I The Pacing Therapies for Congestive Heart Failure (PATH-CHF) Study: Inclusion and Exclusion Criteria Inclusion Criteria ● Dilated cardiomyopathy of either idiopathic or ischemic etiology ● NYHA class III or IV ● Sinus rhythm .55 bpm ● QRS complex duration .120 msec in at least 2 surface ECG leads ● PR interval .150 msec Exclusion Criteria ● Major cardiovascular event, such as myocardial infarction, or had undergone a major surgical procedure such as CABG, within 6 mo of entry into the study ● Uncorrected, primary valvular dysfunction or had valve replacement or reconstruction ● Acute cardiac failure crisis requiring IV inotropes ● Active myocarditis ● Angina during minimal exertion or at rest, or provocable myocardial ischemia within the last 3 mo due to coronary artery disease and amenable to coronary intervention ● Unexplained syncope ● Sustained ventricular tachyarrhythmias requiring antiarrhythmic intervention or an implantable cardioverter defibrillator ● Atrial fibrillation or flutter within the last 6 mo ● Any degree of sinus node dysfunction ● Atrioventricular block higher than Mobitz I or arrhythmias requiring pacemaker implantation ● Hypertrophic obstructive cardiomyopathy ● Clinically significant hepatic or renal disease; uncontrolled diabetes; chronic alcoholism ● Any other known condition other than heart failure that could limit exercise time or survival to ,6 mo CABG 5 coronary artery bypass graft; ECG 5 electrocardiogram; NYHA 5 New York Heart Association.
institutional review board of all 7 participating institutions approved the protocol. Written informed consent was obtained from all patients.
STUDY OBJECTIVES AND MONITORING The goal of the study was to compare the relative benefit of pacing versus no pacing, using objective measures of maximum oxygen consumption, oxygen consumption at anaerobic threshold, 6-minute walk distance, quality-of-life score, left ventricular ejection fraction, and NYHA class. The second objective of this study was to compare the effects of univentricular and biventricular pacing. From a statistical analysis point of view, the 2 pacing modes were tested in a crossover design in which each pacing period was compared with the previous nonpacing period. The 1-month washout period of no pacing, provided before the patient crossed over to the next pacing mode, was expected to provide a baseline comparable to the preimplant condition. However, to ensure the applicability of this study design, the data will be first analyzed for any carryover effects and period effects. In the absence of such effects, the baseline and pacing data will be pooled into their respective groups and evaluated for treatment effect. Since there were no past studies investigating the effects of pacing in CHF, only anecdotal data were available for powering the study endpoints. Accordingly, the study had to include 53 patients to reach statistical significance (with 80% power and 5% sig-
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FIGURE 4. Rate of patient enrollment in the Pacing Therapies in Congestive Heart Failure (PATH-CHF) study. After a very slow enrollment rate over the first year, at least 1 patient per month was enrolled into the study over the last 2 years.
nificance level) with expected differences of 1.5 mL/kg per minute for maximum oxygen consumption and oxygen consumption at anaerobic threshold and 60 m for the 6-minute walk test. Before starting patient recruitment, a data safety monitoring board was constituted and met periodically to review the results. The board was empowered to force early termination of the study if its members observed clinically serious complications. No formal termination rules were adopted before the start of enrollment.
PATIENT ENROLLMENT AND STUDY STATUS The study started in the summer of 1995 with the first patient implant. Starting actively in June 1996, a total of 7 active centers have enrolled 42 patients to date. We expect to complete the study by the end of 1998. Figure 4 shows the overall enrollment rate of the PATH-CHF study. Although several factors contributed to the slow enrollment rate, the primary factors were the restricted inclusion criteria and several ongoing concurrent drug trials in many centers. Acting on request from the Data Safety Monitoring Committee, an interim analysis was performed in the spring of 1998 to assess the difference in benefit between pacing and no pacing. The analysis showed a trend toward improvement in all the primary and secondary endpoints during pacing. Furthermore, there was no trend toward a statistical difference between univentricular and biventricular pacing. The analysis also demonstrated that a minimum number of 35 patients including estimated dropouts were required to show a difference between pacing and no pacing. The difference in benefit with univentricular and biventricular pacing varied widely in many of the endpoints considered. Consequently, we did not attempt to recalculate a sample size to detect a difference between univentricular and biventricular pacing. As a result, the study was focused on only 1 objective, which was to demonstrate statistically significant differences between pacing and no pacing. Acknowledgment: We are indebted to the patients who participated in this trial and to the physicians who
referred their patients for inclusion in the study. We thank the nurses and technicians in the Intensive Care Unit, Heart Failure Program and Surgery of each institution without whose support this study would not have been possible. The investigators acknowledge the help of CHF Research Department of Guidant CRM for their outstanding technical and scientific support in the preparation and execution phase of the study.
APPENDIX The following centers and investigators are participants in the PATH-CHF study: University Hospital, Magdeburg, Germany: Angelo Auricchio, MD, PhD; Helmut Klein, MD; Sybille Grund, MD; Tobias Welte, MD; Christof Huth, MD. RWTH University Hospital, Aachen, Germany: Christoph Stellbrink, MD; Bjo¨rn Diem, MD; Friedrich Scho¨ndube, MD; Peter Hanrath, MD. University Hospital, Essen, Germany: Stefan Sack, MD; Ulrich Wolfhard, MD. University Hospital, Mu¨nster, Germany: Barbara Lamp, MD; Michael Block, MD; Dieter Hammel, MD; Rainer Gradhaus, MD; Dirk Boecker, MD. University Hospital, Skejky Sygehus, Aarhus, Denmark: Peter T. Mortensen, MD, Anders K. Pedersen, MD. “Herz- und Diabeteszentrum NRW”, Bad Oeynhausen, Germany: Kazutomo Minami, MD; Ju¨rgen Vogt, MD; Olaf Kranefeld, MD. University Hospital, Utrecht, the Netherlands: Patricia Bakker, MD; Hans Kirkels, MD.
1. Hochleitner M, Ho¨rtnagl H, Ng CK, Gschnitzer F, Zechmann W. Usefulness of physiologic dual-chamber pacing in drug-resistant idiopathic dilated cardiomyopathy. Am J Cardiol 1990;66:198 –202. 2. Auricchio A, Sommariva L, Salo RW, Scafuri A, Chiariello L. Improvement of cardiac function in patients with severe congestive heart failure and coronary disease by dual-chamber pacing with shortened AV delay. PACE Pacing Clin Electrophysiol 1993;16:2034 –2043. 3. Gold MR, Feliciano Z, Gottlieb SS, Fisher ML. Dual-chamber pacing with short atrio-ventricular delay in congestive heart failure: a randomized study. J Am Coll Cardiol 1995;26:967–973. 4. Linde C, Gadler F, Edner M, Nordlander R, Rosenqvist M, Ryden L. Results of atrioventricular synchronous pacing with optimized delay in patients with severe congestive heart failure. Am J Cardiol 1995;75:919 –923. 5. Bakker PA, Meijburg H, de Jonge N, Van Mechelen R, Wittkamp F, Mower M, Thomas A. Beneficial effects of biventricular pacing in congestive heart failure. (Abstr.) PACE Pacing Clin Electrophysiol 1994;17:820. 6. Cazeau S, Ritter P, Lazarus A, Gras D, Backdach H, Mundler O, Mugica J. Multisite pacing for end-stage heart failure: early experience. PACE Pacing Clin Electrophysiol 1996;19:1748 –1757. 7. Auricchio A, Klein H. Dual-chamber pacing in dilated cardiomyopathy: insufficient sample size, heterogeneous population and inappropriate end points may lead to erroneous conclusions. (Letter.) J Am Coll Cardiol 1996;27:1548. 8. Leitch J, Dear K, Chevalier S, Basta M, Hardy D. Feasibility of measuring the optimal atrioventricular delay. (Abstr.) J Am Coll Cardiol 1997;29:432A. 9. Nishimura RA, Hayes DL, Holmes DR, Tajik AJ. Mechanism of hemodynamic improvement by dual-chamber pacing for severe left ventricular dysfunction: an acute Doppler and catheterization hemodynamic study. J Am Coll Cardiol 1995; 25:281–288. 10. Packer M, Medina N, Yushak M. Hemodynamic changes mimicking a vasodilator drug response in the absence of drug therapy after right heart catheterization in patients with chronic heart failure. Circulation 1985;71:761–766.
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echocardiography. The trial was planned to include 53 patients from 7 centers in Europe over a period of 3 years. The study was divided into 2 parts: acute testing and chronic follow-up. The acute study, performed during the pacemaker implantation, involved extensive testing using a custom-designed computer (FLEXSTIM) and a unique burst pacing protocol (FLEXSTIM protocol) to determine the best ventricular pacing sites and the most appropriate atrioventricular delays. The chronic phase consisted of a crossover study designed to test in each patient the best univentricular pacing site and biventricular pacing as assessed by the acute hemodynamic study. The study started with the first implant in 1995 and has, to date, included 42 patients. The study is expected to be completed by the end of 1998. The results of a first interim analysis showed trends toward improvement in all primary and secondary endpoints during the pacing periods compared with no pacing. Q1999 by Excerpta Medica, Inc. Am J Cardiol 1999;83:130D–135D
acing has been proposed as an adjunct therapy for treatment of symptoms in patients with moderateP to-severe congestive heart failure (CHF). Although
several small studies suggest that the electrical resynchronization of both ventricles, the septum, and the atria may be beneficial in the treatment of CHF patients who continue to deteriorate despite aggressive pharmacologic therapy.2 Although contradictory results have been reported with conventional atrial sequential right ventricular pacing,3,4 more consistent and positive data have been presented when pacing either in the left ventricle or in both ventricles.5,6 Many questions remain concerning the possible use of pacing for the treatment of CHF. Although some patients have benefited from pacing with shortened atrioventricular delays, others have not. This indicates that we do not yet understand the mechanisms involved, the interactions between the pacing site and the applied atrioventricular delay and the patient’s individual characteristics. Past clinical observations provide the rationale for prospective randomized testing of the effect of pacing therapy in CHF. We tested the hypothesis that in patients with moderate-to-severe heart failure and conduction abnormalities, left ventricular or biventricular pacing, at optimum atrioventricular delay, can improve symptoms and can be quantified by objective measures.
the initial report by Hochleitner et al1 could not be confirmed by other investigators, it suggested, for the first time, that electrical stimulation therapy might improve cardiac function. Currently, there is evidence that atrial sequential pacing either in the left or in both ventricles corrects electrical abnormalities and provides symptomatic relief to patients. The results of From the Department of Cardiology, University Hospital, Magdeburg, Germany; Department of Cardiology, University Hospital RWTH, Aachen, Germany; Department of Cardiology, University Hospital, Mu¨nster, Germany; Department of Cardiology, University Hospital, Essen, Germany; Heart Center, Bad Oeynhausen, Germany; University Hospital, Department of Cardiac Surgery, Utrecht, the Netherlands; Department of Cardiology, University Hospital, Aarhus, Denmark. For a complete list of institutions and individuals participating in the PATH-CHF Study Group, see the Appendix. Supported by a grant from Guidant Corporation-Cardiac Rhythm Management, St. Paul, Minnesota. Address for reprints: Angelo Auricchio, MD, PhD, Department of Cardiology, University Hospital, Leipzigerstr. 44, 39120 Magdeburg, Germany.
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©1999 by Excerpta Medica, Inc. All rights reserved.
0002-9149/99/$20.00 PII S0002-9149(99)01014-5
FIGURE 1. Design of Pacing Therapies in Congestive Heart Failure (PATH-CHF) study. After implantation, each patient was randomly assigned to either univentricular or biventricular pacing for 4 weeks followed by 4 weeks of no pacing and then 4 weeks of pacing in the second mode. At the end of 12 weeks, each patient was followed every other month for up to 1 year.
OVERVIEW OF THE STUDY DESIGN The design of the Pacing Therapies in Congestive Heart Failure (PATH-CHF) study is shown in Figure 1. The study consisted of 4 phases: (1) an evaluation phase before implant; (2) an acute testing phase using the FLEXSTIM during the implantation procedure; (3) a randomized crossover protocol that tests 2 different pacing modes with a no pacing (washout) period in between; and (4) a chronic pacing phase. Preimplant evaluation: The preoperative measurements included a review of medical history, physical examination, biochemical testing, chest x-ray, resting electrocardiogram, 24-hour Holter monitoring, echocardiogram, 6-minute walk exercise test, and completion of a quality-of-life questionnaire (“Living with Heart Failure” Questionnaire, University of Minnesota). The frequency and duration of previous hospital admissions due to cardiac events were recorded. In addition, patient activity was recorded using 2 surface accelerometers taped to the skin at the left pectoral and apical site. A right and left cardiac catheterization was performed in all patients to exclude possible organic heart disease amenable to cardiac surgery or to percutaneous coronary angioplasty. Intraoperative phase: At the time of the pacemaker implantation all patients underwent an acute testing using the FLEXSTIM (Guidant CRM, St. Paul, MN) computer. The main objective of the intraoperative testing was to guide the selection of the optimal atrioventricular delay and pacing site for the chronic phase. The procedure was performed while the patients were under general anesthesia. Chronic pacing leads were implanted as described below (see Implant Options). After femoral arterial and venous puncture using the Seldinger technique, patients were instrumented with two 8Fr dual micromanometer catheters (Model SPC780c; Millar Instruments, Houston, TX) in both sides of
the heart to provide right atrial, right ventricular, aortic, and left ventricular pressures. Pressure catheters and pacing leads were connected to the FLEXSTIM computer, which was designed to execute a randomized pacing protocol, acquire hemodynamic signals, and provide offline comparative analysis of the hemodynamic parameters collected during the pacing interventions. The rationale for the FLEXSTIM protocol was to measure the cardiac response to pacing. In fact, a controlled study to determine the effect of pacing chamber and atrioventricular delay is technically difficult because of the large number of possible pacing combinations. The analysis of the acute hemodynamic effects of pacing using the standard methodology (e.g., cardiac output determined by thermodilution7 or by Doppler examination8) is time consuming and may not provide sufficient data for meaningful statistical comparisons of the different pacing sites and atrioventricular delays in a single patient. Group statistics will be misleading when there are large interactions between individuals and pacing variables.9 In addition, normal physiologic changes in baseline during the study period must be taken into account.10 The FLEXSTIM protocol consists of periods of pacing in biventricular pacing (VDD) mode (i.e., atrial sensing followed by ventricular pacing, after an atrioventricular delay) separated by periods of no pacing in normal sinus rhythm in a 5 paced beat/15 nonpaced beat duty cycle (Figure 2). When pacing and no pacing sequences were interrupted by a premature ventricular contraction, additional beats were added to allow the premature ventricular contraction beat and surrounding beats to be removed from the analysis. Pacing was performed in the right ventricle, left ventricle, or right and left ventricles (biventricular 5 BV) simultaneously, at 5 different atrioventricular delays. The 5 atrioventricular delays were equally distributed
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FIGURE 2. Schematic representation of the FLEXSTIM computer and accessories (upper panel ) and pacing protocol used to test multiple combinations of pacing site and atrioventricular (AV) delay treatment combinations (lower panel ). The average of 6 baseline beats is represented by B and each paced beat is shown as Pn, where n can be 2, 3, 4, or 5. BiV 5 biventricular; LV 5 left ventricular; RV 5 right ventricular.
between 0 msec to 30 msec less than the patient’s intrinsic PR interval as measured by the intracardiac electrograms. Each treatment combination of pacing chamber and atrioventricular delay was repeated 5 times in random order for each patient. The entire sequence summed to 1,500 beats, which, at an average heart rate of 75 beats/min, required 20 minutes. Raw data were recorded on a 14-bit TEAC digital tape recorder (Model RD-130TE; TEAC America, Montebello, CA ) with sampling at 12,000 Hz and then down-sampled to 500 Hz for detailed offline analysis. Several hemodynamic parameters were automatically measured with custom signal analysis software (Guidant CRM). To compare pacing chambers and atrioventricular delays, an offline analysis of aortic diastolic pressure, aortic systolic pressure, pulse pressure, and left ventricular peak positive dP/dt (left ventricle 1dP/dt) was used. Implant options: To evaluate the relative chronic benefits of right or left ventricular, and biventricular pacing, we implanted standard right atrial and right ventricular endocardial pacing leads together with an 132D THE AMERICAN JOURNAL OF CARDIOLOGYT
epicardial pacing lead, positioned on the surface of the left ventricle. Currently, none of the pacemakers available can sense in the atrium and simultaneously pace both ventricles while maintaining flexibility to independently program atrioventricular delay and ventricular site (right or left ventricular or biventricular). Consequently, we considered a few implant options to pace both ventricles. The so-called split cathode requires the connection of a Y adapter to the pacemaker header to split the unipolar cathodal electrode into 2 arms. The right and left ventricles would be stimulated in parallel, but this would not give the option to switch between single chamber and biventricular pacing. On the other hand, the extended bipole or the connection of a bipolar Y adapter connected to the pacemaker header retains the capability to switch between single chamber and biventricular pacing by programming the pulse generator from unipolar to bipolar. Although chronic testing of all modes (right or left ventricular, or biventricular pacing) would not be possible, a comparison of biventricular pacing versus either one of the single chambers could be achieved. However, some
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FIGURE 3. Chest x-ray of a patient enrolled into the Pacing Therapies in Congestive Heart Failure (PATH-CHF) study. Pacemaker implanted in the right pectoral position (Vigor 1) was connected to a right atrial lead (RA 1) and to an endocardial right ventricular lead (RV endo). The pacemaker placed in the left pectoral position (Vigor 2) was connected to a second right atrial lead (RA 2) and to an epicardial screw-in lead (LV epi).
clinical data indicated increases in pacing threshold using this pacing modality with a high probability of losing capture in the anodal polarity of the bipole. Therefore, the only remaining possibility for implementing biventricular pacing with currently available hardware required implantation of 2 pulse generators, each one being connected to a right atrial lead and to a ventricular lead. Univentricular pacing could be obtained by setting the ventricular channel of 1 pulse generator to pace in unipolar (VDD) mode and the ventricular channel of the second pulse generator to pace in bipolar mode. Due to the fact that all the ventricular leads were unipolar, programming 1 pulse generator ventricular output to bipolar results in no output from the ventricular lead. Biventricular pacing could be initiated by setting 1 pulse generator to VDD mode while the other was programmed in VVT mode. Voltage outputs for each pulse generator could be adjusted according to each individual lead. All patients were implanted with 2 DDDR pacemakers (Vigor DDDR or Discovery DDDR; Guidant CRM). The first pacemaker was implanted and connected to a right atrial bipolar lead (Sweet-Tip, Guidant) and to a unipolar right ventricular lead (Sweet-Tip, Guidant). The second pacemaker was implanted and connected to a second bipolar right atrial lead and a unipolar left ventricular epicardial lead (Model 4316, Guidant or Model 4965, Medtronic, Minneapolis, MN) (Figure 3). For the duration of the study 4 different settings were allowed. A sequential
right atrium– univentricular pacing (right or left ventricle) was achieved by programming the first pacemaker in DDD mode and the second pacemaker in VVI mode at 30 beats/min with bipolar ventricular output. The lower rate limit of the DDD pacemaker was set at 40 beats/min to ensure back-up pacing, and the atrioventricular delay was set according to the results of the intraoperative testing. Atrial sequential biventricular pacing was obtained by programming 1 pacemaker in DDD mode (same setting as described above) and the second pacemaker in VVT mode. When no pacing therapy was desired, 1 pacemaker was programmed to VVI at 30 beats/min with bipolar ventricular output and the second pacemaker to VVI at 40 beats/min with unipolar ventricular output. The unipolar ventricular output setting with a low lower rate limit in 1 pacemaker allowed back-up pacing if required. Study procedures: At the time of discharge from the hospital, each patient proceeded into a randomized (1 : 1 ratio) chronic crossover study that involved testing of 2 pacing modes versus no pacing over a period of 12 weeks (Figure 1). The randomization procedure included 2 arms, one beginning with sequential atriouniventricular (right or left ventricle whichever was best, according to the acute study) pacing and the second one beginning with sequential atrio-biventricular (simultaneous right and left ventricular) pacing. After 4 weeks of pacing (week 0 – 4 of treatment), the pacemakers were programmed to no pacing for the next 4 weeks (week 4 – 8 of treatment) in all patients.
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After 4 weeks of no pacing, the patients were again paced over a period of 4 weeks (week 8 –12 of treatment). The programmed mode was then sequential atrio-biventricular if the patient was initially assigned to sequential atrio-univentricular pacing during the first 4 weeks of treatment, and vice-versa for the other arm of randomization. Early termination of each 4-week period of treatment could occur if the patient’s condition met the specified guidelines for crossing over to the next pacing mode. Although the study was completed after 12 weeks, all patients were followed clinically on a bimonthly basis up to 1 year after the implantation. Before reprogramming to another pacing mode (termination of each 4 weeks of treatment or clinically indicated early termination of the treatment period), all patients underwent a clinical examination, chest x-rays, and blood examination. In addition, a symptom-limited cardiopulmonary exercise test, a 6-minute walk test, ambulatory electrocardiographic monitoring, a quality-of-life questionnaire (Minnesota Living with Heart Failure Questionnaire), and an echocardiography examination were performed. Guidelines for crossover to the next mode: We recognized that complications or problems might occur that could affect the study protocol. In general, a patient had to complete the designated duration of each pacing mode before crossing over to the next mode. If there were atrial sensing problems or lead dislodgment that prevented consistent VDD pacing, we attempted to troubleshoot and correct the sensing problem by eventually repositioning the lead. If atrial sensing could be reinstated to permit consistent VDD pacing, the current pacing mode was restarted. If atrial sensing could not be reinstated, the patient was excluded from further participation in the study. The patients could also refuse a crossover or demand to be returned to a previous mode if they could discern a difference in symptoms from one pacing mode to the next. In such cases, the patient was programmed to the requested mode and was removed from the crossover portion of the study. However, the investigator continued to follow the patient on a bimonthly basis to evaluate the long-term effects of pacing therapy. Finally, if the patient’s condition worsened during any mode in the chronic phase, the investigator made every effort to treat the patient medically according to standard medical practice without disrupting the protocol. However, if the patient’s condition worsened significantly and hospitalization was required, the patient could be withdrawn from the current pacing mode, treated until stable, and eventually advanced to the next portion of the protocol.
PATIENT SELECTION All patients enrolled in the study had symptoms of moderate-to-severe heart failure with New York Heart Association (NYHA) classification of III (for at least 6 months) or IV, despite treatment at the maximum tolerated dosage with diuretics, angiotensin-converting enzyme inhibitors, digitalis, vasodilators or nitrates, and b blockers. The complete list of inclusion and exclusion criteria can be found in Table I. The 134D THE AMERICAN JOURNAL OF CARDIOLOGYT
TABLE I The Pacing Therapies for Congestive Heart Failure (PATH-CHF) Study: Inclusion and Exclusion Criteria Inclusion Criteria ● Dilated cardiomyopathy of either idiopathic or ischemic etiology ● NYHA class III or IV ● Sinus rhythm .55 bpm ● QRS complex duration .120 msec in at least 2 surface ECG leads ● PR interval .150 msec Exclusion Criteria ● Major cardiovascular event, such as myocardial infarction, or had undergone a major surgical procedure such as CABG, within 6 mo of entry into the study ● Uncorrected, primary valvular dysfunction or had valve replacement or reconstruction ● Acute cardiac failure crisis requiring IV inotropes ● Active myocarditis ● Angina during minimal exertion or at rest, or provocable myocardial ischemia within the last 3 mo due to coronary artery disease and amenable to coronary intervention ● Unexplained syncope ● Sustained ventricular tachyarrhythmias requiring antiarrhythmic intervention or an implantable cardioverter defibrillator ● Atrial fibrillation or flutter within the last 6 mo ● Any degree of sinus node dysfunction ● Atrioventricular block higher than Mobitz I or arrhythmias requiring pacemaker implantation ● Hypertrophic obstructive cardiomyopathy ● Clinically significant hepatic or renal disease; uncontrolled diabetes; chronic alcoholism ● Any other known condition other than heart failure that could limit exercise time or survival to ,6 mo CABG 5 coronary artery bypass graft; ECG 5 electrocardiogram; NYHA 5 New York Heart Association.
institutional review board of all 7 participating institutions approved the protocol. Written informed consent was obtained from all patients.
STUDY OBJECTIVES AND MONITORING The goal of the study was to compare the relative benefit of pacing versus no pacing, using objective measures of maximum oxygen consumption, oxygen consumption at anaerobic threshold, 6-minute walk distance, quality-of-life score, left ventricular ejection fraction, and NYHA class. The second objective of this study was to compare the effects of univentricular and biventricular pacing. From a statistical analysis point of view, the 2 pacing modes were tested in a crossover design in which each pacing period was compared with the previous nonpacing period. The 1-month washout period of no pacing, provided before the patient crossed over to the next pacing mode, was expected to provide a baseline comparable to the preimplant condition. However, to ensure the applicability of this study design, the data will be first analyzed for any carryover effects and period effects. In the absence of such effects, the baseline and pacing data will be pooled into their respective groups and evaluated for treatment effect. Since there were no past studies investigating the effects of pacing in CHF, only anecdotal data were available for powering the study endpoints. Accordingly, the study had to include 53 patients to reach statistical significance (with 80% power and 5% sig-
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FIGURE 4. Rate of patient enrollment in the Pacing Therapies in Congestive Heart Failure (PATH-CHF) study. After a very slow enrollment rate over the first year, at least 1 patient per month was enrolled into the study over the last 2 years.
nificance level) with expected differences of 1.5 mL/kg per minute for maximum oxygen consumption and oxygen consumption at anaerobic threshold and 60 m for the 6-minute walk test. Before starting patient recruitment, a data safety monitoring board was constituted and met periodically to review the results. The board was empowered to force early termination of the study if its members observed clinically serious complications. No formal termination rules were adopted before the start of enrollment.
PATIENT ENROLLMENT AND STUDY STATUS The study started in the summer of 1995 with the first patient implant. Starting actively in June 1996, a total of 7 active centers have enrolled 42 patients to date. We expect to complete the study by the end of 1998. Figure 4 shows the overall enrollment rate of the PATH-CHF study. Although several factors contributed to the slow enrollment rate, the primary factors were the restricted inclusion criteria and several ongoing concurrent drug trials in many centers. Acting on request from the Data Safety Monitoring Committee, an interim analysis was performed in the spring of 1998 to assess the difference in benefit between pacing and no pacing. The analysis showed a trend toward improvement in all the primary and secondary endpoints during pacing. Furthermore, there was no trend toward a statistical difference between univentricular and biventricular pacing. The analysis also demonstrated that a minimum number of 35 patients including estimated dropouts were required to show a difference between pacing and no pacing. The difference in benefit with univentricular and biventricular pacing varied widely in many of the endpoints considered. Consequently, we did not attempt to recalculate a sample size to detect a difference between univentricular and biventricular pacing. As a result, the study was focused on only 1 objective, which was to demonstrate statistically significant differences between pacing and no pacing. Acknowledgment: We are indebted to the patients who participated in this trial and to the physicians who
referred their patients for inclusion in the study. We thank the nurses and technicians in the Intensive Care Unit, Heart Failure Program and Surgery of each institution without whose support this study would not have been possible. The investigators acknowledge the help of CHF Research Department of Guidant CRM for their outstanding technical and scientific support in the preparation and execution phase of the study.
APPENDIX The following centers and investigators are participants in the PATH-CHF study: University Hospital, Magdeburg, Germany: Angelo Auricchio, MD, PhD; Helmut Klein, MD; Sybille Grund, MD; Tobias Welte, MD; Christof Huth, MD. RWTH University Hospital, Aachen, Germany: Christoph Stellbrink, MD; Bjo¨rn Diem, MD; Friedrich Scho¨ndube, MD; Peter Hanrath, MD. University Hospital, Essen, Germany: Stefan Sack, MD; Ulrich Wolfhard, MD. University Hospital, Mu¨nster, Germany: Barbara Lamp, MD; Michael Block, MD; Dieter Hammel, MD; Rainer Gradhaus, MD; Dirk Boecker, MD. University Hospital, Skejky Sygehus, Aarhus, Denmark: Peter T. Mortensen, MD, Anders K. Pedersen, MD. “Herz- und Diabeteszentrum NRW”, Bad Oeynhausen, Germany: Kazutomo Minami, MD; Ju¨rgen Vogt, MD; Olaf Kranefeld, MD. University Hospital, Utrecht, the Netherlands: Patricia Bakker, MD; Hans Kirkels, MD.
1. Hochleitner M, Ho¨rtnagl H, Ng CK, Gschnitzer F, Zechmann W. Usefulness of physiologic dual-chamber pacing in drug-resistant idiopathic dilated cardiomyopathy. Am J Cardiol 1990;66:198 –202. 2. Auricchio A, Sommariva L, Salo RW, Scafuri A, Chiariello L. Improvement of cardiac function in patients with severe congestive heart failure and coronary disease by dual-chamber pacing with shortened AV delay. PACE Pacing Clin Electrophysiol 1993;16:2034 –2043. 3. Gold MR, Feliciano Z, Gottlieb SS, Fisher ML. Dual-chamber pacing with short atrio-ventricular delay in congestive heart failure: a randomized study. J Am Coll Cardiol 1995;26:967–973. 4. Linde C, Gadler F, Edner M, Nordlander R, Rosenqvist M, Ryden L. Results of atrioventricular synchronous pacing with optimized delay in patients with severe congestive heart failure. Am J Cardiol 1995;75:919 –923. 5. Bakker PA, Meijburg H, de Jonge N, Van Mechelen R, Wittkamp F, Mower M, Thomas A. Beneficial effects of biventricular pacing in congestive heart failure. (Abstr.) PACE Pacing Clin Electrophysiol 1994;17:820. 6. Cazeau S, Ritter P, Lazarus A, Gras D, Backdach H, Mundler O, Mugica J. Multisite pacing for end-stage heart failure: early experience. PACE Pacing Clin Electrophysiol 1996;19:1748 –1757. 7. Auricchio A, Klein H. Dual-chamber pacing in dilated cardiomyopathy: insufficient sample size, heterogeneous population and inappropriate end points may lead to erroneous conclusions. (Letter.) J Am Coll Cardiol 1996;27:1548. 8. Leitch J, Dear K, Chevalier S, Basta M, Hardy D. Feasibility of measuring the optimal atrioventricular delay. (Abstr.) J Am Coll Cardiol 1997;29:432A. 9. Nishimura RA, Hayes DL, Holmes DR, Tajik AJ. Mechanism of hemodynamic improvement by dual-chamber pacing for severe left ventricular dysfunction: an acute Doppler and catheterization hemodynamic study. J Am Coll Cardiol 1995; 25:281–288. 10. Packer M, Medina N, Yushak M. Hemodynamic changes mimicking a vasodilator drug response in the absence of drug therapy after right heart catheterization in patients with chronic heart failure. Circulation 1985;71:761–766.
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