European Journal of Heart Failure

European Journal of Heart Failure 2002 4(3):311-320; doi:10.1016/S1388-9842(02)00018-1

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© 2002 European Society of Cardiology

Cardiac resynchronization therapy in advanced heart failure the multicenter InSync clinical study

Daniel Gras^*, Christophe Leclercq, Anthony S.L. Tang, Cliff Bucknall, Henk Oude Luttikhuis and Anders Kirstein-Pedersen

Unité de Soins et de Cardiologie Interventionnelle Polyclinique Saint Henri, Place Beaumanoir, 44100 Nantes, France

^* Corresponding author. Tel.: +33-2-4044-2528; fax: +33-2-4044-2524. E-mail address: dangras{at}aol.com

	Abstract

Top Notes Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Appendix A Acknowledgments References

 
Background: recent short-term observations have shown an improvement in cardiac function and heart failure symptoms from atrio-biventricular pacing. This study was designed to assess the safety and feasibility of an atrio-biventricular transvenous pacing system, and examine the long-term effects of cardiac resynchronization in patients with advanced heart failure and ventricular conduction abnormalities.

Methods and results: between August, 1997 and November, 1998, 103 patients received a cardiac resynchronization system (CRS) consisting of a pulse generator interfaced with an atrio-biventricular lead system, including a lead designed for left ventricular (LV) pacing via cardiac veins. Baseline evaluation included 12-lead electrocardiogram, estimation of New York Heart Association (NYHA) functional class, assessment of quality of life (QOL), and distance covered during a 6-min walk (6-MW). Detailed echocardiographic data were also collected in a subset of 46 patients. Measurements were repeated in all surviving patients at 1, 3, 6 and 12 months after implantation of the CRS. A single, self-limiting procedure-related complication occurred. Over a follow-up of 12 months, 21 patients died. The 12-month actuarial survival was 78% (CI 70–87%). Nine surviving patients were withdrawn from the study during long-term follow-up for miscellaneous reasons. At each point of follow-up, a significant shortening of QRS duration was measured. In addition, significant improvements were observed in mean NYHA functional class, 6-MW and QOL score. In the 46 patients with complete echocardiographic data, LV ejection fraction increased from 21.7±6.4% at baseline to 26.1±9.0% at last follow-up (P=0.006), LV end diastolic dimension decreased from 72.7±9.2 to 71.6±9.1 mm (P=0.233), interventricular mechanical delay decreased from 27.5±32.1 to 20.3±25.5 ms (P=0.243), mitral regurgitation apical four-chamber area decreased from 7.66±5.5 to 6.69±5.9 cm² (P=0.197), and left ventricular filling time increased from 363±127 to 408±111 ms (P=0.002). Conclusions: long-term cardiac resynchronization can be safely and reliably achieved by transvenous atrial synchronized right and left ventricular pacing. These changes were accompanied by clinically relevant improvements in functional status and QOL, as well as a measurable increase in LV performance. The outcome of randomised controlled trials is awaited.

Key Words: 6-MW, 6-min walk • ECG, electrocardiogram • ECHO, echocardiogram • LV, left ventricular • CRS, cardiac resynchronization system • NYHA, New York Heart Association • QOL, quality of life • RV, right ventricular

Received December 21, 2001; Accepted January 14, 2002

	1. Introduction

Top Notes Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Appendix A Acknowledgments References

 
Dilated cardiomyopathy, characterized by enlargement of the cardiac chambers and depressed ventricular function, is a common cause of heart failure and is associated with high mortality [1–3]. This condition is increasing in prevalence with the aging population of most societies. As a result of a better understanding of the underlying pathophysiologic mechanisms responsible for the progression of the disorder, major advances have been achieved in the management of both cardiac symptoms and triggering factors that lead to worsening of ventricular function. Current therapeutic options, consisting mainly of drug therapy, have expanded remarkably over the past few years with the introduction of angiotensin converting enzyme inhibitors and beta adrenergic blockers for the treatment of heart failure [4]. However, a sizable number of patients continue to suffer from limited survival and poor quality of life due to severe limitations during effort and daily activities [4]. Ventricular conduction defects, as evidenced by a QRS duration>120 ms and/or left bundle branch block, are common in the advanced heart failure population [5,6]. Furthermore, ventricular conduction defects are associated with adverse hemodynamic consequences [7,8] and impair cardiac function. Cardiac resynchronization therapy has recently been proposed as a new approach to the management of heart failure associated with ventricular conduction defects [9–12]. The purpose of this study was to examine the feasibility, safety, and long-term effects of cardiac resynchronization therapy in patients with advanced heart failure and ventricular conduction abnormalities.

	2. Methods

Top Notes Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Appendix A Acknowledgments References

 
2.1. Patient population and data collection
InSync was a prospective observational multicenter European and Canadian study. Its inclusion and exclusion criteria are listed in Table 1. Between August, 1997 and November, 1998, 117 patients were enrolled into the study. Before undergoing implantation of the cardiac resynchronization system (CRS), each patient underwent a complete evaluation including: (a) 12-lead surface electrocardiogram (ECG) for measurement of QRS complex duration; (b) estimation of New York Heart Association (NYHA) functional class; (c) assessment of quality of life (QOL) by the Minnesota Living with Heart Failure questionnaire score; and (d) distance covered during a 6-min walk (6-MW). In addition, detailed and paired echocardiographic data were obtained in a subset of 46 patients. This study was approved by a Medical Ethics Committee at each participating institution, and all subjects provided informed consent.

View this table: [in this window] [in a new window]   Table 1 Patient selection criteria

 
2.2. Cardiac resynchronization system and implantation
The CRS consists of a pulse generator (InSync^® model 8040, Medtronic Inc., Minneapolis, MN) interfaced with an atrio-biventricular transvenous lead system, including a lead (Attain^TM, models 2187 or 2188, Medtronic Inc., Minneapolis, MN) designed to achieve left ventricular (LV) pacing from an epicardial vein accessed via the coronary sinus. Right atrial and ventricular pacing was performed with standard lead models and insertion techniques. The pulse generator header includes a triple connector system for the separate interface of right atrial, right ventricular (RV), and LV leads, and allows the simultaneous delivery of pacing pulses to both right and left ventricles. As a rule, attempts were made to place the LV lead preferentially into a lateral or postero-lateral venous tributary (Fig. 1), or, if unsuccessful, into the great cardiac vein as a second choice, or the mid-cardiac vein as a last resort. Implantation of the CRS was successful in 103 out of 117 patients (88%). Causes of unsuccessful implantation included: inability to catheterize the coronary sinus (two patients), inability to advance the lead to its final venous destination (five patients), unstable lead position (three patients), and unacceptably high pacing threshold (four patients). These 14 patients were excluded from further analyses. Before the patient's discharge from the hospital and at each follow-up evaluation, the atrioventricular pacing interval was individually adjusted to optimize hemodynamic function examined during Doppler echocardiography [13,14]. Clinical outcome measures, including QRS duration, NYHA functional class, 6-MW distance and QOL, were collected in all surviving patients at 1, 3, 6 and 12 months after implantation of the CRS. In addition, detailed long-term echocardiographic measurements were available in 46 patients

View larger version (98K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 (a) Right atrial (RA), right ventricular (RV) and left ventricular (LV) lead position on antero-posterior chest roentgenogram. The LV lead has been advanced through the coronary sinus into a lateral venous tributary. RA and RV leads have been placed in a standard manner. (b) Same electrode deployment as in (a) viewed on right lateral roentgenogram.

 
2.3. Statistical analyses
All results are presented as mean values±standard deviation (S.D.). Data from the baseline, and the 1, 3, 6 and 12 month follow-up visits were included. A repeated measures analysis of variance was performed on the data for NYHA classification, 6-MW distance, QOL, and QRS interval. Comparisons of echocardiographic measurements were made between baseline and values measured at a mean last follow-up of 2.6±0.8 months. When overall significance was obtained at =0.05, Tukey's Studentized range test was used for all possible pairwise comparisons of follow-up visits.

	3. Results

Top Notes Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Appendix A Acknowledgments References

 
3.1. Patient characteristics
The baseline clinical characteristics of the 103 successfully implanted patients are listed in Table 2. Implantation of the CRS was performed solely for the purpose of heart failure management in 96 patients. In 7 patients, the system was implanted for the dual purpose of management of congestive heart failure and antibradycardia pacing. Among the entire cohort, 66 patients (64%) were >65 years of age. The study population's cardioactive drug regimen upon entry into the study consisted of diuretics in 93% of patients, angiotensin converting enzyme inhibitors in 70%, angiotensin II receptor agonists in 16%, digoxin in 58%, beta adrenergic blockers in 17%, vasodilators in 17%, calcium channel blockers in 15%, amiodarone in 50%, anticoagulants in 34% and intravenous inotropic support in 2% of patients. Table 3 lists the observations gathered at the time of CRS implantation.

View this table: [in this window] [in a new window]   Table 2 Baseline clinical characteristics of study population

 

View this table: [in this window] [in a new window]   Table 3 CRS implant characteristics and immediate LV lead performance

 
3.2. Clinical outcome measures
3.2.1. QRS duration
Before cardiac resynchronization, mean QRS duration was markedly prolonged at 178±28 ms. With resynchronization, mean QRS duration was reduced to 149±23 ms at 1 month. Fig. 2 is a representative example of the shortening of QRS duration which was observed during biventricular pacing versus during intrinsic rhythm. This reduction in mean QRS duration was maintained throughout the twelve month follow-up to 151±26 ms at 3 months, 153±21 ms at 6 months and 152±24 ms at 12 months, and was statistically significant at all time points when compared to baseline (Fig. 3).

View larger version (127K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Narrowing of the QRS complex during biventricular pacing compared to patient's intrinsic rhythm. Standard 12-lead electrocardiograms are shown for each. Recording speed=50 mm/s.

 

View larger version (7K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 QRS druation at baseline and achieved with cardiac resynchronizations therapy maintained for 1-year follow-up. *P<0.001.

 
3.2.2. NYHA functional class
At baseline, 70 patients (68%) were in NYHA functional class III and 33 patients (32%) were in class IV, corresponding to a mean of 3.3±0.4. Cardiac resynchronization therapy was followed by a decrease in mean NYHA functional class to 2.4±0.79 at 1 month. This reduction, which persisted at 3 (2.2±0.79), 6 (2.1±0.80) and 12 months (2.2±0.68), was statistically significant when compared to baseline (Fig. 4).

View larger version (9K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 4 Sustained decrease in mean NYHA functional class up to 1-year compared to baseline. *P<0.001.

 
3.2.3. Six-minute walk distance
Distance covered during 6-MW was 290±108 m prior to initiation of cardiac resynchronization therapy. At 1 month of follow-up, the mean distance covered during the test was significantly increased to 361±104 m. This improvement, which persisted at 3 (364±107 m), 6 (378±124 m), and 12 months (365±103 m) was statistically significant when compared to baseline (Fig. 5). It is noteworthy that 25 patients were unable to perform a 6-MW test at baseline due to the severity of heart failure symptoms. Of these 25 patients, 19 subsequently became capable of performing the test at follow-up visits, covering an average of 395±130 m (range 100–700). These patients were not included in the above analysis.

View larger version (7K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 5 Distance walked in 6 min at baseline and up to 1-year follow-up. *P<0.001.

 
3.2.4. QOL assessment
Patient's self-assessment of QOL at baseline was severely impaired, as evidenced by a mean score of 53±20 points by the Minnesota Living with Heart Failure Questionnaire. At 1 month, the mean score had decreased significantly to 31±19 points. This decrease in mean QOL score, which persisted at 3 (33±19 points), 6 (31±22 points) and 12 months (31±19 points), was statistically significant when compared to baseline (Fig. 6).

View larger version (7K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 6 Improvement in quality of life scores assessed by the Minnesota Living with Heart Failure questionnaire up to 1-year of follow-up. *P<0.001 vs. baseline.

 
3.2.5. Echocardiographic data
In 46 patients, serial high quality echocardiographic images were available for measurement of the long-term effects of cardiac resynchronization on cardiac function. Table 4 compares the baseline characteristics of this subset of patients with those of the remaining population. No significant difference was found in any of the variables between the two groups. Table 5 presents the changes in echocardiographic indices of cardiac function between baseline and an average of 2.6±0.8 months of follow-up. These measurements were indicative of a significant improvement in LV systolic function, effective cardiac resynchronization, and decrease in mitral regurgitation.

View this table: [in this window] [in a new window]   Table 4 Baseline demographic and clinical characteristics of 46 patients with complete paired echocardiographic data vs. remaining patient population (n–57)

 

View this table: [in this window] [in a new window]   Table 5 Changes in echocardiographic measurements between baseline and last follow-up of resynchronization therapy in 46 patients with available paired data sets (two-tailed paired comparisons)

 
3.3. Complications, adverse effects and survival
A single procedure-related complication occurred among the 117 patients, consisting of a perforation of a coronary sinus tributary without any clinical manifestation, and requiring no further intervention. Nine patients were withdrawn from the study during long-term follow-up for the following reasons: loss of biventricular pacing capture occurred in three patients, who underwent no further intervention; three patients underwent cardiac transplantation, one within days of CRS implantation, and the other two patients at 152 and 357 days of follow-up; one patient underwent removal of the entire CRS due to early infection of the RV lead; one patient suffered from diaphragmatic stimulation by the LV lead, which could not be corrected by reprogramming of the pulse generator; one patient required removal of the CRS because of intolerably painful pulse generator pocket. In ten patients, 13 procedures were needed within 3 months of follow-up to reposition (n=7) or replace (n=6) a dislodged LV lead. Dislodgment of the LV lead occurred in three additional patients who exited the study as described previously. Over the 1-year follow-up, 21 patients died (Table 6). The 12-month actuarial survival was 78% (95% CI 70–87%, Fig. 7).

View this table: [in this window] [in a new window]   Table 6 Causes of death in 21 patients up to 12 months of follow-up

 

View larger version (6K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 7 Twelve-month actuarial survival of InSync population.

 

	4. Discussion

Top Notes Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Appendix A Acknowledgments References

 
This observational study suggests that in patients with advanced heart failure and ventricular conduction abnormalities, cardiac resynchronization results in improvements, sustained for at least 1 year, in NYHA functional class, distance covered in 6-MW test, and QOL score. This study population receiving cardiac resynchronization therapy is so far the largest reported in the literature, with the longest follow-up. It is noteworthy that 64% of the study patients were older than 65 years, and consequently, unlikely to derive benefit from currently available alternative therapies such as cardiac transplantation.

Several factors must be kept in mind when interpreting the results of this study. First, patients were systematically selected on the basis of ventricular dysynchrony defined as a QRS complex >150 ms. Thus, patients without major ventricular conduction defects were deliberately excluded from the study since they were not expected to derive a clinical benefit from cardiac resynchronization therapy. Second, meticulous attempts were made to place the LV lead into a lateral or posterior-lateral coronary sinus tributary. These positions are believed to be the optimal LV pacing sites, as gauged by shortened QRS and improved hemodynamic parameters [15,16]. Finally, the AV interval was individually adjusted to optimize LV filling.

4.1. Rationale for cardiac resynchronization therapy in heart failure
Standard dual chamber pacing with short AV delay was first proposed as a therapy for patients with dilated cardiomyopathy with encouraging preliminary results [17]. Initial enthusiasm was rapidly tempered when carefully conducted randomised controlled studies failed to validate these results [18–20]. This may be due to a competing effect of improvement in left ventricular filling against the adverse hemodynamic effects of right ventricular apical pacing [21,22]. Ventricular dysynchrony, manifested by a prolonged QRS duration and, typically, a left bundle branch block morphology on the surface ECG, is due to abnormal electrical activation, which results in an abnormal sequence of ventricular contraction and alters left ventricular mechanical performance. The clinical consequences of ventricular dysynchrony are attributable to several direct effects on mechanical function, including delayed LV activation, uncoordinated ventricular electrical activation, compromised LV filling, and prolonged systolic mitral regurgitation [7,8,23]. These observations form the basis of resynchronization therapy to correct the electrical and mechanical cardiac dysynchrony and improve the cycle-by-cycle regulation of LV filling and ejection. Thus, a pacing system offering optimal ventricular filling (appropriate AV delay) and ventricular resynchronization (biventricular pacing) would likely be more beneficial for heart failure therapy. Acute hemodynamic studies of cardiac resynchronization in patients with severe heart failure demonstrated an increase in cardiac index compared with atrial-only or dual-chamber RV pacing and optimal AV delay [24,25], a significant decrease in pulmonary capillary wedge pressure [24,26], and improvement of LV mechanics [27]. Smaller and shorter-term studies also reported some aspect of clinical improvement in heart failure symptoms and exercise performance [12,28,29]. This study represents a more thorough, longer-term evaluation of cardiac resynchronization therapy for patients with advanced heart failure and ventricular conduction abnormalities. The sustained improvements in functional status and QOL, as well as the low complication rate associated with this therapy, are encouraging. The 22% 1-year mortality in this study is similar to recent reports involving comparable patient groups [2,3,15,30,31].

4.2. Study limitations
This study was observational and did not include a comparison group of untreated patients. However, before the launch of strictly randomized trials, pioneering treatment strategies need to undergo an initial evaluation of their safety and feasibility. This study began at a time when no data had been collected or published on the clinical value of cardiac resynchronization therapy. In pursuance of these encouraging results, several randomized studies are currently in progress [32–35].

Assessment of QOL and NYHA functional class is open to subjective biases on the part of both patients and caregivers. The treatment effect on these relatively soft endpoints will need confirmation in larger, longer-term, controlled trials. On the other hand, the observation of clear improvements in functional capacity is particularly noteworthy in such a population of patients who had remained intractable despite the most vigorous available pharmacological combinations. The impact of cardiac resynchronization therapy on patient survival is currently unknown, and is also being tested in ongoing randomized multicenter studies as mentioned earlier.

	5. Conclusions

Top Notes Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Appendix A Acknowledgments References

 
The encouraging results recorded in this prospective, multicenter study justify pursuing the evaluation of cardiac resynchronization therapy as a supplemental treatment of heart failure. The completion of ongoing randomized controlled trials will further define the role of this therapy as well as the profile of the patients most likely to benefit from this new and promising treatment.

	Appendix A

Top Notes Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Appendix A Acknowledgments References

 
The following investigators and clinical centers participated in the InSync clinical study: K.H. Tscheliessnigg, D. Petussnigg, Chirurgische Universitatsklinik, Graz, Austria; A. Kirstein-Pedersen, Cardiological Department, Arhus, Denmark; P.H.L. Djiane, J.C. Deharo, Hôpital Sainte Marguerite, Marseille, France; D. Gras, S. Cazeau, P. Ritter, A. Lazarus, Clinique Bizet, Paris, France; P. Mabo, C. Leclercq, C. Alonso, C. Daubert, Centre Cardio-Pneumologique, Rennes, France; M. Wieczorek, Herzzentrum Kaiser Wilhelm Krankenhausen, Duisburg, Germany; A. Puglisi, Ospedale Fatabenefratelli, Roma, Italy; P.A. Ravazzi, Ospedale SS Antonio e Bagio, Alessandria, Italy; J. Silvestre Hospital Universitario La Paz, Madrid, Spain; H.A. Oude Luttikhuis, St. Sophia Ziekenhuis, Zwolle, The Netherlands; P. Holt, C. Bucknall, R. Chatoor, St. Thomas Hospital, London, UK; V.E. Paul, Harefield Hospital, London, UK; J.D. Skeehan, The Glenfield Hospital, Leicester, UK; D. Cameron, H. Ross, R.J. Cusimano, S. Mohamed, P. Liu, T. Parker, Toronto Hospital, Toronto, Canada; S. Kimber, D. Manyari, D. Taylor, L. daSilva, A. van Schaik, S. Galomhusien, D. Humen, K. Kavanagh, University of Alberta Hospital, Alberta, Canada; A.S.L. Tang, S. Smith, K. Chan, C. Carey, P. Theoret-Patrick, University of Ottawa Institute, Ottawa, Canada; M. Talajic, B. Thibault, J.L. Rouleau, D. Roy, J.C. Tardif, L. Lavoie, E. Guilbault, Montreal Heart Institute, Montreal, Canada. The following Medtronic, Inc. personnel were involved in the clinical management of the trial: A. Vetter, M. van Trigt, C. Struble, I. Wijngaarden-Smaling, J. Hartog, G. Aguezoum, S. Unger, S. McCarville, D. Smith, W. VanHout, S. Petersen-Stejskal and M.R.S. Hill.

	Acknowledgments

Top Notes Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Appendix A Acknowledgments References

 
This study was supported by a grant from Medtronic Inc., Minneapolis, MN.

	Notes

Top Notes Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Appendix A Acknowledgments References

 
For the InSync Investigators.

	References

Top Notes Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Appendix A Acknowledgments References

 

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