032201 effects of multisite biventricular pacing in patients

B I V E N T R I C U L A R PAC I N G I N PAT I E N T S W I T H H E A R T FA I LU R E A N D I N T R AV E N T R I C U L A R C O N D U C T I O N D E L AY
EFFECTS OF MULTISITE BIVENTRICULAR PACING IN PATIENTS WITH
HEART FAILURE AND INTRAVENTRICULAR CONDUCTION DELAY
SERGE CAZEAU, M.D., CHRISTOPHE LECLERCQ, M.D., THOMAS LAVERGNE, M.D., STUART WALKER, M.D., CHETAN VARMA, M.D., CECILIA LINDE, M.D., STÉPHANE GARRIGUE, M.D., LUKAS KAPPENBERGER, M.D., GUY A. HAYWOOD, M.D., MASSIMO SANTINI, M.D., CHRISTOPHE BAILLEUL, PH.D., AND JEAN-CLAUDE DAUBERT, M.D., FOR THE MULTISITE STIMULATION IN CARDIOMYOPATHIES (MUSTIC) STUDY INVESTIGATORS* ABSTRACT
HE aging of the population has made chron- Background
ic heart failure an increasingly important heart failure have electrocardiographic evidence of a health problem.1 It is the leading medical major intraventricular conduction delay, which may cause of hospitalization, and its economic worsen left ventricular systolic dysfunction through cost continues to increase. Despite important thera- asynchronous ventricular contraction. Uncontrolled peutic advances with angiotensin-converting–enzyme studies suggest that multisite biventricular pacing im- (ACE) inhibitors2,3 or angiotensin II–receptor block- proves hemodynamics and well-being by reducing ers,4 beta-blockers,5 and spironolactone,6 the prognosis ventricular asynchrony. We assessed the clinical ef- of patients with chronic heart failure remains poor.
ficacy and safety of this new therapy.
Methods
The benefit of medical treatment is probably short- Sixty-seven patients with severe heart fail- ure (New York Heart Association class III) due to chron- lived, merely delaying the inevitable progression to ic left ventricular systolic dysfunction, with normal heart failure that is refractory to drug treatment. As sinus rhythm and a duration of the QRS interval of the disorder progresses, the well-being and exercise more than 150 msec, received transvenous atriobiven- tolerance of patients deteriorate dramatically, and the tricular pacemakers (with leads in one atrium and each rates of hospitalization increase. Nonpharmacologic ventricle). This single-blind, randomized, controlled therapies (such as heart transplantation and the use crossover study compared the responses of the pa- of implantable assist devices) are considered only in tients during two periods: a three-month period of in- the later stages of the disease,8,9 but access to such active pacing (ventricular inhibited pacing at a basic rate of 40 bpm) and a three-month period of active It was against this backdrop of limited resources (atriobiventricular) pacing. The primary end point wasthe distance walked in six minutes; the secondary end and the need for less expensive and simpler alternatives points were the quality of life as measured by ques- that resynchronization therapy by means of multisite tionnaire, peak oxygen consumption, hospitalizations biventricular pacing was proposed.10 The rationale for related to heart failure, the patients’ treatment prefer- this therapy is based on the high (30 to 50 percent) ence (active vs. inactive pacing), and the mortality rate.
prevalence of intraventricular conduction delay among Results
patients with heart failure11-13 and on the resultant study before randomization, and 10 failed to complete poor coordination of ventricular contraction and re- both study periods. Thus, 48 patients completed both laxation,14-16 which in turn enhances the hemodynamic phases of the study. The mean (±SD) distance walked consequences of chronic left ventricular systolic dys- in six minutes was 23 percent greater with active pac- function. Short-term studies have shown that atriobi- ing (399±100 m vs. 326±134 m, P<0.001), the quality- ventricular pacing (with leads in one atrium and each of-life score improved by 32 percent (P<0.001), peakoxygen uptake increased by 8 percent (P<0.03), hos- ventricle) significantly improves hemodynamics by re- pitalizations were decreased by two thirds (P<0.05), ducing ventricular asynchrony.17-23 Results from un- and active pacing was preferred by 85 percent of the controlled studies of permanent biventricular pac- Conclusions
Although it is technically complex, atri- obiventricular pacing significantly improves exercise From InParys, Saint-Cloud, France (S.C.); the Centre Cardio-Pneu- mologique, Centre Hospitalier Universitaire, Rennes, France (C. Leclercq, tolerance and quality of life in patients with chronic J.-C.D.), Hôpital Broussais, Paris (T.L.); Harefield Hospital, Harefield, heart failure and intraventricular conduction delay.
United Kingdom (S.W.); St. George’s Hospital, London (C.V.); Karolinska Hospital, Stockholm, Sweden (C. Linde); Hôpital Cardiologique du HautLevêque, Bordeaux, France (S.G.); Centre Hospitalier Universitaire Vau- Copyright 2001 Massachusetts Medical Society.
dois, Lausanne, Switzerland (L.K.); Derriford Hospital, Plymouth, UnitedKingdom (G.A.H.); Ospedale San Filippo Neri, Rome (M.S.); and ELARecherche, Le Plessis Robinson, France (C.B.). Address reprint requests toDr. Daubert at the Département de Cardiologie et Maladies Vasculaires,Centre Cardio-Pneumologique, Hôpital Pontchaillou–Centre HospitalierUniversitaire, 35033 Rennes CEDEX, France, or at [email protected].
Other authors were Philippe Mabo, M.D. (Centre Cardio-Pneu- mologique); Arnaud Lazarus, M.D. (InParys); Philippe Ritter, M.D.
(Hôpital Broussais); Terry Levy, M.D. (Harefield Hospital); and WilliamMcKenna, M.D. (St. George’s Hospital).
*The members of the study group are listed in the Appendix.
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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne ing24-26 show a sustained improvement in terms of with stratification according to study center. The single-blind, cross- symptoms, exercise tolerance, and well-being. In con- over phase (active vs. inactive) then began, followed by a period dur- trast, univentricular, right-sided pacing in patients with ing which the pacing system was programmed according to thepreference of the patient (on the basis of the two periods during the sinus rhythm has been found to benefit only a small crossover phase). Only the results from the crossover phase are re- subgroup of patients.27-29 The aim of this single-blind, randomized, controlled crossover study was to assessthe clinical efficacy and safety of transvenous atriobi- Implantation of Pacemakers
ventricular pacing in patients with severe heart failure All leads were implanted transvenously. The atrial lead was placed and major intraventricular conduction delay but with- high in the right atrium. The left ventricular lead was placed in atributary of the coronary sinus, according to a previously described out standard indications for a pacemaker.30 method.31 Specially designed electrodes were used. A venogramhelped to optimize the position of the lead. The target site was pref- erably the lateral wall, midway between base and apex, but other Selection of Patients
lateral or posterior sites were also acceptable. The great cardiac veinor the middle cardiac vein was used only when other sites were not All patients gave their written informed consent before enroll- accessible. The right ventricular lead was positioned as far as pos- ment. All had severe heart failure due to idiopathic or ischemic left sible from the left ventricular lead. The pacemakers were triple-out- ventricular systolic dysfunction, an ejection fraction of less than put devices that made use of standard dual-chamber technology, 35 percent, and an end-diastolic diameter of more than 60 mm.
with built-in adapters to synchronize the pacing of the two ventri- All patients were in sinus rhythm with a QRS interval of more than cles (Chorum 7336 MSP, ELA Medical, Montrouge, France, and 150 msec and without a standard indication for insertion of a pace- InSync 8040, Medtronic, Minneapolis). Results of the implanta- maker.30 Before study entry, patients had been in New York Heart tions were assessed from the positions of the leads on chest x-ray Association (NYHA) class III for at least one month while receiving films and from changes in the width of the QRS interval on 12-lead the optimal treatment, including at least diuretics and ACE inhib- itors at the maximal tolerated dose.
The criteria for exclusion were hypertrophic or restrictive car- Programming of Pacemakers
diomyopathy, suspected acute myocarditis, correctable valvulopathy, At randomization, the pacemaker was programmed to be either an acute coronary syndrome lasting less than three months, recent inactive or active. The basic pacing rate was set at 40 bpm and the coronary revascularization (during the previous three months) or upper rate limit at 85 percent of the maximal predicted heart rate scheduled revascularization, treatment-resistant hypertension, severe according to the age and sex of the patient. Each patient underwent obstructive lung disease, an inability to walk, reduced life expect- Doppler echocardiography to determine the optimal atrioventric- ancy not associated with cardiovascular disease (less than one year), ular delay (electrical delay between atrial and ventricular excitation) or an indication for the implantation of a cardioverter–defibrillator.30 Study Design
Medication
The trial involved 15 centers in Europe; the study protocol was No modification in medication other than adjustment of the dose approved by local ethics committees in the six participating coun- of diuretic was permitted between the time of enrollment and the tries. Enrollment began in March 1998 and was completed one year end of the crossover phase of the study. Compliance was monitored later. The study included a six-month randomized crossover phase, by means of follow-up interviews and prescription checks.
during which atriobiventricular (active) pacing was compared withventricular inhibited (inactive) pacing at a basic rate of 40 bpm, Evaluation of Patients
each for a period of three months in random order (Fig. 1). Implan-tation was performed after a one-month observation period to ver- At base line, the time of randomization, and the end of each of ify the stability of heart failure (defined as no need to change treat- the two periods during the crossover phase, the patients were eval- ment and no change in functional class). After implantation, the uated according to the distance walked in six minutes, the quality of pacemaker was programmed to be inactive. Patients were random- life as assessed with use of the Minnesota Living with Heart Failure ly assigned to study groups within the following two weeks, after questionnaire,33 the NYHA classification, the need for medication, the proper performance of the pacing system had been ascertained.
the need for hospitalization, 12-lead surface electrocardiography, Randomization of the order of treatment followed a block design and cardiopulmonary exercise testing.
Figure 1. Design of the Study.
Patients were randomly assigned to three months each of inactive pacing (ventricular, inhibited at abasic rate of 40 bpm) and active pacing (atriobiventricular). CO1 denotes the end of crossover period1, and CO2 the end of crossover period 2.
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B I V E N T R I C U L A R PAC I N G I N PAT I E N T S W I T H H E A R T FA I LU R E A N D I N T R AV E N T R I C U L A R C O N D U C T I O N D E L AY
The six-minute-walk test was carried out according to the recom- All analyses were based on the intention-to-treat principle. Thus, mendations of Guyatt and colleagues and Lipkin et al.34,35 Base- all enrolled patients were included in the analysis, but each efficacy line evaluation included a training test to confirm that the patient end point could be assessed only in patients with no data missing could complete the six-minute-walk test. Each visit included two after the completion of both crossover phases. Base-line character- tests with an interval of at least three hours between them. The istics were assessed with the use of the chi-square test for dichot- maximal difference between the two tests was 15 percent, and the omous variables and Student’s t-test or Wilcoxon’s nonparametric value recorded was the mean of the results of the two tests.
test for quantitative or categorical variables. The responses obtained The Minnesota questionnaire33,36 contains 21 questions regarding for all criteria assessing clinical efficacy were compared with the use patients’ perception of the effects of heart failure on their daily lives.
of the Wilcoxon test and according to a two-period and two-treat- Each question is rated on a scale of 0 to 5, producing a total score ment (two-by-two) crossover design. Period and carryover effects between 0 and 105. The higher the score, the worse the quality were checked before the efficacy of treatment was evaluated. Mor- bidity and mortality were compared during the first crossover pe-riod and were described for all other phases of the study. The sta- End Points
bility of the results was assessed by a per-protocol analysis, whichincluded only patients without any deviations from the protocol.
The primary end point was the distance walked in six minutes.
The threshold of significance was set at 0.05.
The main secondary end point was the quality of life. Other second-ary end points were peak oxygen uptake, hospital admissions because of decompensated heart failure, the patient’s preference with re-gard to pacing (active vs. inactive) at the end of the crossover phase, Study Population
Sixty-seven patients (50 men and 17 women) with a mean age of 63 years were included in the study.
Statistical Analysis
Heart failure was of ischemic origin in 25 patients. All On the basis of previous reports of mortality rates in patients in patients were in NYHA class III at the time of enroll- NYHA class III, we estimated a 10 percent mortality rate at six ment, despite the use of optimal treatment, including months. Moreover, we expected a 10 percent rate of failure of the ACE inhibitors or the equivalent in 96 percent of pa- implantation of the left ventricular lead and a 20 percent rate of pre-mature termination because of loss of left ventricular pacing effica- tients, diuretics in 94 percent, digoxin in 48 percent, cy or unstable heart failure. We estimated that there would be a 10 amiodarone in 31 percent, beta-blockers in 28 percent, percent increase in the distance walked in six minutes with active and spironolactone in 22 percent. The main base-line pacing. For a study with a 95 percent confidence level and 95 per- characteristics of the patients are listed in Table 1.
cent power, the total target sample needed was estimated to be 22patients. For the Minnesota quality-of-life score, a predicted 10 per- Implantation
cent reduction with active pacing necessitated a 30-patient sample.
However, considering the estimated mortality and dropout rates, Three patients withdrew from the study before im- we determined that a 40-patient sample was needed.
plantation, two because of unstable heart failure (one TABLE 1. CLINICAL CHARACTERISTICS OF THE STUDY POPULATION AT BASE LINE
CHARACTERISTIC
AT BASE LINE
AT RANDOMIZATION
Peak oxygen uptake (ml/kg of body 13.7±3.9 *Plus–minus values are means ±SD. In the first study group, the pacemaker was programmed to be active first and then inactive. In the second study group, the pacemaker was programmed to beinactive first and then active.
†P values are for the comparison between the two study groups at randomization.
‡A higher score indicates a poorer quality of life (range, 0 to 105).
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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne of whom subsequently died) and one because of a The Minnesota score decreased by a mean of 32 preexisting indication for pacing. Implantation of a percent (P<0.001) with active pacing (Fig. 3). Peak left ventricular lead was attempted in 64 patients, oxygen uptake increased by a mean of 8 percent (P< with a 92 percent success rate. A lateral position was 0.03). No significant carryover and period effects were reached in 80 percent of the patients, and the mean (±SD) pacing threshold was 1.4±1.1 V. Early dis- Because of the crossover design, hospitalizations lodgment occurred in eight patients and was suc- were analyzed in the first period only. Three hospital- cessfully corrected in five. Overall, 88 percent of the izations for heart failure occurred during active pac- patients had a functional left ventricular lead at the ing, as compared with nine during inactive pacing Study Dropouts and Randomization
Patients’ Preferences
Six additional patients were removed from the study At the end of the crossover phase, the patients — before randomization, five because of failed implanta- who had no knowledge of the order of treatment — tion of the left ventricular lead and one because of sud- were asked which three-month period they had pre- den death while the device was inactive. Therefore, 58 ferred. Forty-one (85 percent) preferred the period patients were randomly assigned to and equally distrib- corresponding to the active-pacing mode (P<0.001), uted between two study groups. There were no signif- two (4 percent) preferred the period corresponding to icant differences in the main clinical characteristics be- the inactive-pacing mode, and five (10 percent) had no At randomization, the width of the QRS complex had acutely decreased by a mean of 10 percent with active pacing (157±30 msec, as compared with 174± Ten patients did not complete the two crossover 20 msec during spontaneous rhythm; P<0.002). The periods, including five who did not complete the first optimal atrioventricular delay was 108±43 msec.
period. One withdrew his consent at the time of ran-domization. Two had uncorrectable loss of left ven- Clinical Results
tricular pacing efficacy. During inactive pacing, one Results are shown in Table 2. During the active patient had severe decompensation leading to a pre- phase, the mean distance walked in six minutes was mature switch to active pacing. One patient died sud- 23 percent longer (P<0.001) than during the inactive denly after 26 days of active pacing.
phase (Fig. 2). In the per-protocol analysis, which During the second crossover period, five additional included 23 patients, the mean distance walked was patients dropped out, including three for worsening 375±83 m during the inactive period, as compared heart failure. The only instance of decompensation with 424±83 m during the active period (P<0.004).
with active pacing was attributed to rapidly progres- TABLE 2. THE DISTANCE WALKED IN SIX MINUTES, THE PEAK OXYGEN UPTAKE,
AND THE QUALITY-OF-LIFE SCORE (ASSESSED WITH THE MINNESOTA LIVING WITH HEART FAILURE QUESTIONNAIRE) AFTER THREE MONTHS OF INACTIVE OR ACTIVE PACING.* TOTAL NO. OF
STUDY GROUP
PATIENTS
ACTIVE PACING
INACTIVE PACING
*Plus–minus values are means ±SD. In the first study group, the pacemaker was programmed to be active first and then inactive. In the second study group, the pacemaker was programmed to beinactive first and then active.
†A higher score indicates a poorer quality of life (range, 0 to 105).
‡P<0.001 for the comparison with active pacing.
§P=0.029 for the comparison with active pacing.
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B I V E N T R I C U L A R PAC I N G I N PAT I E N T S W I T H H E A R T FA I LU R E A N D I N T R AV E N T R I C U L A R C O N D U C T I O N D E L AY
Figure 2. Distance Walked in Six Minutes at Specified Times during the Study.
The mean (±SD) values are given for each part of the study. CO1 denotes the end of crossover period1, and CO2 the end of crossover period 2.
Figure 3. Quality-of-Life Score (Assessed with the Minnesota Living with Heart Failure Questionnaire)
at Specified Times during the Study.
The mean (±SD) values are given for each phase of the study. CO1 denotes the end of crossover period1, and CO2 the end of crossover period 2. A higher score indicates a poorer quality of life (range, 0 to 105).
sive aortic stenosis. One patient died from acute my- ber of deaths was three during the six-month cross- ocardial infarction a few hours after a premature switch to active pacing because of severe decompensation.
Another patient had decompensation as persistent DISCUSSION
atrial fibrillation occurred during inactive pacing. One This study shows that ventricular resynchronization patient died suddenly two hours after switching from significantly improves exercise tolerance and the qual- inactive to active pacing. Finally, one patient withdrew ity of life in patients with severe heart failure who have from the study because of lung cancer. The total num- sinus rhythm and major intraventricular conduction N Engl J Med, Vol. 344, No. 12 · March 22, 2001 · www.nejm.org · 877
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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne delay but who do not have a standard indication for end, a crossover design was chosen. This design, which makes every patient his or her own control, is prob- To be included, patients had to have been in NYHA ably ideal for the initial evaluation of such a therapeu- class III for at least one month. The purpose of this tic intervention, whereas parallel trials that require a criterion was to select patients whose condition was large study population are better suited to the assess- stable enough for them to withstand a 7.5-month ment of treatments that have shown promise in earlier study, including a 6-month crossover phase. Earlier, crossover trials and to the evaluation of long-term uncontrolled studies24 showed that despite clinical morbidity and mortality. A potential downside of the improvement, mortality remained high in patients in crossover design is that the treatments administered class IV whose condition was unstable, as compared during the first period may have a carryover effect in with the much lower mortality in patients who were the second period. In this study, analysis revealed the in class III at the time of implantation.
absence of any significant carryover effect for the main Optimal medical therapy principally involved two selected end points. Another methodologic issue is the classes of drugs: ACE inhibitors (or angiotensin II– possible influence of study dropouts on results, but receptor blockers) and diuretics, prescribed at the a per-protocol analysis found a significant difference maximal tolerated doses in 98 percent of patients.
in the primary end point in favor of active pacing.
Conversely, beta-blockers and spironolactone were Exercise tolerance (as indicated by the six-minute- prescribed to many fewer patients, since these two walk test) was chosen as the primary end point. Peak drugs were not recognized as effective treatments for oxygen uptake, measured during cardiopulmonary ex- severe heart failure when the study protocol was ap- ercise testing, has been considered as a reference meas- proved.5,6 No changes in treatment were permitted urement in patients with heart failure,38,39 which can between the time of inclusion and the end of the be used to assess the maximal exercise tolerance. How- crossover phase. We were therefore able to conclude ever, this variable only remotely reflects the function- that any clinical changes noted during the crossover al impairment endured during activities of daily life.
periods were induced by the pacing modes, by the Furthermore, peak oxygen uptake can be interpreted natural history of the disease, or by both.
only by a sophisticated technique whose reproduc- Ventricular asynchrony was assessed by electrocar- ibility must be ascertained — a fact that may restrict diography and defined as a QRS interval of more than its practical use in multicenter trials. Therefore, the 150 msec during the intrinsic conduction. This em- distance walked in six minutes, which correlates with pirical choice was later supported by studies of acute the peak oxygen uptake,40,41 was chosen as the primary hemodynamic changes,21-23 which showed that atriobi- end point. The use of this test to assess the effect of ventricular or atrial–left ventricular pacing had ben- therapy in previous studies42 showed that the minimal eficial effects, mostly in patients with an intrinsic QRS variation required to confirm with 99 percent confi- dence that a real change has occurred is 10 percent.
Cardiac-resynchronization therapy requires simul- This threshold of 10 percent was used in our study taneous stimulation of both ventricles, in synchrony to determine the sample size. In fact, we observed a with atrial activity. The main technical difficulty is to mean global difference of 23 percent in favor of ac- ensure reliable left ventricular pacing. Early attempts at permanent biventricular pacing10,18,22 used an epi- The Minnesota questionnaire introduced by Rec- cardial lead implanted in the left ventricle by thora- tor et al.33 is commonly used for the assessment of cotomy or thoracoscopy, but the transvenous route patients with heart failure, and its clinical value has quickly became the standard procedure.31 After cath- been established.36 The quality-of-life score from this eterization of the coronary sinus, the transvenous ap- questionnaire was defined as the main secondary end proach permits insertion of the lead into an epicardial point in this study. The mean global difference in this vein over the left ventricular free wall; experience with score observed between the two pacing modes was the procedure and improvements in lead technology 32 percent. The magnitude of improvement for both have dramatically increased the success rate of implan- the distance walked in six minutes and the quality-of- tation. The optimal site of implantation, however, life score was greater than that previously seen in drug remains to be determined. Results from short-term trials of the same duration and with similar patients.36,43 studies37 suggest that the lateral wall, midway between In contrast, the results with respect to mortality and base and apex, is optimal. In our study, this target morbidity should be interpreted with caution in this location was reached in 80 percent of the patients.
relatively small study, which had limited follow-up.
Finally, the reliability of the transvenous route was The significantly lower number of hospitalizations confirmed, because 88 percent of the patients had a with atriobiventricular pacing during the first cross- functional lead in the left ventricle at the end of the over period is encouraging, but it involves only a short time. Mortality was 7.5 percent (5 of 67 patients) This trial was designed primarily to assess the clin- during the 7.5 months of the protocol, but random- ical efficacy of multisite biventricular pacing. To that ized studies involving a large number of patients and 878 · N Engl J Med, Vol. 344, No. 12 · March 22, 2001 · www.nejm.org
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B I V E N T R I C U L A R PAC I N G I N PAT I E N T S W I T H H E A R T FA I LU R E A N D I N T R AV E N T R I C U L A R C O N D U C T I O N D E L AY
extended follow-up will be necessary to reach con- of current treatment of heart failure. Lancet 1998;352:Suppl I:SI19- clusions regarding the morbidity and mortality asso- SI28.
9. Goldstein DJ, Oz MC, Rose EA. Implantable left ventricular assist de-
ciated with atriobiventricular pacing.
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In conclusion, our results support the therapeutic 10. Cazeau S, Ritter P, Bakdach S, et al. Four chamber pacing in dilated
cardiomyopathy. Pacing Clin Electrophysiol 1994;17:1974-9.
value of ventricular resynchronization in patients who 11. Aaronson KD, Schwartz JS, Chen TM, Wong KL, Goin JE, Mancini
have severe heart failure and major intraventricular DM. Development and prospective validation of a clinical index to predict conduction delay. Atriobiventricular pacing significant- survival in ambulatory patients referred for cardiac transplant evaluation. Circulation 1997;95:2660-7.
ly improved symptoms, exercise tolerance, and the 12. Shamim W, Francis DP, Yousufuddin M, et al. Intraventricular conduc-
quality of life and was associated with a reduced num- tion delay: a prognostic marker in chronic heart failure. Int J Cardiol 1999; ber of hospitalizations for decompensated heart fail- 70:171-8.
13. Wilensky RL, Yudelman P, Cohen AI, et al. Serial electrocardiographic
ure. However, further studies are needed to assess the changes in idiopathic dilated cardiomyopathy confirmed at necropsy. Am J long-term clinical effect of this therapeutic approach.
Cardiol 1988;62:276-83.
14. Grines LC, Bashore TM, Boudoulas H, Olson S, Shafer P, Wooley CF.
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Supported by ELA Recherche, Medtronic and the Swedish Heart and interventricular asynchrony. Circulation 1989;79:845-53.
Lung Association and by a grant from the Swedish Medical Research 15. Xiao HB, Brecker SJ, Gibson DG. Effects of abnormal activation on
the time course of left ventricular pressure pulse in dilated cardiomyopathy. During the study, Drs. Cazeau, Kappenberger, and Daubert were paid consultants for Medtronic, and Dr. Cazeau was also a paid consultant for 16. Ziao HB, Lee CH, Gibson DG. Effect of left bundle branch block on
ELA Recherche. Dr. Bailleul is an employee of ELA Recherche who was diastolic function in dilated cardiomyopathy. Br Heart J 1991;66:443-7.
temporarily on leave during the study period.
17. Foster AH, Gold MR , McLaughlin JS. Acute hemodynamic effects of
atrio-biventricular pacing in humans. Ann Thorac Surg 1995;59:294-300.
18. Cazeau S, Ritter P, Lazarus A, et al. Multisite pacing for end-stage
We are indebted to the European Society of Cardiology, owner of heart failure: early experience. Pacing Clin Electrophysiol 1996;19:1748- data from the MUSTIC study; and to the Centre Hospitalier Uni- versitaire de Rennes, promoter of the study in France. 19. Blanc JJ, Etienne Y, Gilard M, et al. Evaluation of different ventricular
pacing sites in patients with severe heart failure. Circulation 1997;96:3273-
APPENDIX
7.
20. Leclercq C, Cazeau S, Le Breton H, et al. Acute hemodynamic effects
The following persons participated in the study: Study Board: J.-C.
of biventricular DDD pacing in patients with end-stage heart failure. J Am Daubert (chair), C. Linde (cochair), C. Bailleul, S. Cazeau, L. Kappen- berger, R. Sutton; Safety and Adverse Events Committee: C. Alonso, H.J.
21. Kass DA, Chen CH, Curry C, et al. Improved left ventricular mechan-
Dargie, P. Lechat; Independent Statistics Center: J.-S. Hulot, P. Lechat; ics from acute VDD pacing in patients with dilated cardiomyopathy and Technical Advisers: D. Gras, P. Ritter, S. Walker; Core Analysis Center: C.
ventricular conduction delay. Circulation 1999;99:1567-73.
Alonso, Rennes, France (electrocardiography and Holter monitoring), D.
22. Auricchio A, Stellbrink C, Block M, et al. Effect of pacing chamber
Gibson, London (echocardiography), C. Linde, Stockholm, Sweden (qual- and atrioventricular delay on acute systolic function of paced patients with ity of life), and W. McKenna, London (cardiopulmonary exercise test); congestive heart failure. Circulation 1999;99:2993-3001.
Monitoring and Data Management Team: C. Bailleul (study manager), K.
23. Nelson GS, Curry CW, Wyman BT, et al. Predictors of systolic aug-
Coombs, C. Fournier, M. Limousin (ELA Recherche), L. Mollo, S.
mentation from left ventricular preexcitation in patients with dilated car- Myrum (Medtronic), J.-M. Torralba, M.-C. Vandrell; Investigators — France: diomyopathy and intraventricular conduction delay. Circulation 2000;101: E. Aliot, S. Cazeau, J. Clémenty, J.-C. Daubert, C. De Chillou, J.-C. De- haro, P. Djiane, S. Garrigue, D. Gras, L. Guize, M. Jarwe, S. Kacet, D.
24. Daubert JC, Cazeau S, Leclercq C. Do we have reasons to be enthu-
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