cardaic resynchronization

8/8/2019 CARDAIC RESYNCHRONIZATION

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n engl j med 352;15 www.nejm.org april 14, 2005

The new england journal of

medicine

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original article

The Effect of Cardiac Resynchronization

on Morbidity and Mortality in Heart Failure

John G.F. Cleland, M.D., Jean-Claude Daubert, M.D.,Erland Erdmann, M.D., Nick Freemantle, Ph.D., Daniel Gras, M.D.,

Lukas Kappenberger, M.D., and Luigi Tavazzi, M.D.,for the Cardiac Resynchronization Heart Failure (CARE-HF) Study Investigators*

From the Department of Cardiology, Castle

Hill Hospital, Kingston-upon-Hull, UnitedKingdom (J.G.F.C.); the Department ofCardiology, Hpital Pontchaillou, Rennes,France (J.-C.D.); Klinik III fr Innere Medi-zin der Universitt zu Kln, Cologne, Ger-many (E.E.); the University of Birmingham,Edgbaston, United Kingdom (N.F.); Nou-velles Cliniques Nantaises, Nantes, France(D.G.); the Division of Cardiology, CentreHospitalier Universitaire Vaudois, Lau-sanne, Switzerland (L.K.); and Istituto diRicovero e Cura a Carattere Scientifico,Policlinico San Matteo, Pavia, Italy (L.T.).Address reprint requests to Dr. Cleland atthe Department of Cardiology, Castle HillHospital, University of Hull, Kingston-upon-Hull, United Kingdom, or at j.g.cleland@

hull.ac.uk.

*The CARE-HF Study investigators arelisted in the Appendix.

This article was published at www.nejm.org on March 7, 2004.

N Engl J Med 2005;352:1539-49.

Copyright 2005 Massachusetts Medical Society.

background

Cardiac resynchronization reduces symptoms and improves left ventricular function in

many patients with heart failure due to left ventricular systolic dysfunction and cardiacdyssynchrony. We evaluated its effects on morbidity and mortality.

methods

Patients with New York Heart Association class III or IV heart failure due to left ventricu-lar systolic dysfunction and cardiac dyssynchrony who were receiving standard pharma-

cologic therapy were randomly assigned to receive medical therapy alone or with cardiacresynchronization. The primary end point was the time to death from any cause or anunplanned hospitalization for a major cardiovascular event. The principal secondary end

point was death from any cause.

results

A total of 813 patients were enrolled and followed for a mean of 29.4 months. The pri-

mary end point was reached by 159 patients in the cardiac-resynchronization group, ascompared with 224 patients in the medical-therapy group (39 percent vs. 55 percent;hazard ratio, 0.63; 95 percent confidence interval, 0.51 to 0.77; P


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espite improvements in pharma-

cologic treatment, many patients withheart failure have severe and persistent

symptoms, and their prognosis remains poor.

1,2

Such patients commonly have regions of delayedmyocardial activation and contraction, leading to

cardiac dyssynchrony. In a series of trials lasting upto six months, cardiac resynchronization decreased

symptoms and improved exercise capacity, the qual-ity of life, and ventricular function.

3-7

The Compar-

ison of Medical Therapy, Pacing, and Defibrillationin Heart Failure (COMPANION) trial showed thatcardiac-resynchronization therapy alone or com-

bined with an implantable defibrillator reduced thecomposite end point of death from any cause or hos-

pitalization during a mean follow-up of 16 months

8

;however, the decrease in the risk of death was not

significant with cardiac resynchronization therapyalone (P=0.06). Meta-analyses have left lingering

uncertainty about the effects of cardiac resynchro-nization on the risk of complications and death.

9,10

We analyzed the effects of cardiac resynchroniza-

tion on the risk of complications and death amongpatients who were receiving standard medical ther-

apy for moderate or severe heart failure and cardiacdyssynchrony.

The Cardiac Resynchronization Heart Failure(CARE-HF) trial was a multicenter, international,

randomized trial comparing the effect on the risk

of complications and death of standard pharmaco-logic therapy alone with that of the combination of

standard therapy and cardiac resynchronization(without a defibrillator) in patients with left ventric-

ular systolic dysfunction, cardiac dyssynchrony, andsymptomatic heart failure.

11-13

Patients were en-

rolled at 82 European centers; enrollment began inJanuary 2001 and ended in March 2003. The studywas not blinded. The members of the end-points

committee (see the Appendix), however, were notaware of patients treatment assignments. Patients

in the control group were not scheduled to receive adevice, both for ethical reasons and so that the trial

could assess the entire effect of cardiac resynchro-nization, including complications associated withimplantation of the device.

11-13

The steering committee (see the Appendix) de-signed the trial. The Medtronic Corporation funded

the trial and provided a study manager to superviseits conduct. Data were sent by investigators to core

laboratories or to an independent clinical-research

organization (Quintiles, Dublin) that maintained

the database, issued data-clarification forms, andassisted by Medtronic employees, verified sourcedocuments. The sponsor had no access to the data-

base and did not participate in the analysis of the re-sults or the writing of the article. All analyses were

performed by one of the authors with the assistanceof an independent statistician. Three Medtronic rep-

resentatives commented on the manuscript beforeits submission. The study was approved by the local

ethics committee of each participating institutionand by appropriate national ethics committees. Allpatients provided written informed consent.

patients

Eligible patients were at least 18 years of age, hadhad heart failure for at least six weeks, and were in

New York Heart Association (NYHA) class III or IVdespite receipt of standard pharmacologic therapy,

with a left ventricular ejection fraction of no morethan 35 percent, a left ventricular end-diastolic di-mension of at least 30 mm (indexed to height), and

a QRS interval of at least 120 msec on the electro-cardiogram. Patients with a QRS interval of 120 to

149 msec were required to meet two of three addi-tional criteria for dyssynchrony: an aortic preejec-tion delay of more than 140 msec, an interventric-

ular mechanical delay of more than 40 msec, ordelayed activation of the posterolateral left ventric-

ular wall.

11-13

Patients who had had a major cardiovascular

event in the previous six weeks, those who had con-

ventional indications for a pacemaker or an im-plantable defibrillator, and those with heart fail-

ure requiring continuous intravenous therapy wereexcluded. Also excluded were patients with atrial ar-

rhythmias, since such patients cannot benefit fromthe atrial component of resynchronization.

11-13

study procedures

Randomization was stratified according to the

NYHA class and was carried out by Quintiles withthe use of a minimization procedure. Patients who

were randomly assigned to undergo cardiac resyn-chronization received a Medtronic InSync or InSync

III device, which provided atrial-based, biventricularstimulation with the use of standard right ventricu-lar and Attain (Medtronic) left ventricular leads. In-

vestigators were asked to position the left ventricularlead to pace the lateral or posterolateral left ventric-

ular wall transvenously and provide radiographicdocumentation. Backup atrial pacing was set at 60

beats per minute. The interventricular delay was set

d

m et h ods

The New England Journal of Medicine

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Copyright 2005 Massachusetts Medical Society. All rights reserved.


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effect of cardiac resynchronization on heart failure

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to zero, and the atrioventricular delay was echocar-

diographically optimized.

11

Patients were moni-tored overnight after receiving the device. If theinitial procedure failed, repeated attempts at im-

plantation were encouraged, and expert assistancewas provided.

follow-up

Patients were evaluated at 1, 3, 6, 9, 12, and 18months and every six months thereafter, and stan-

dard medications were adjusted as appropriate atthese visits. Investigators were asked to report alladverse events, which were classified in a blinded

fashion by an end-points committee or, if they wereprocedure-related or device-related, by an indepen-

dent expert who was not blinded to the study-groupassignments (see the Appendix).

The protocol required follow-up to continue for18 months after the last patient had been enrolled,

unless the data and safety monitoring board stoppedthe study earlier or fewer than 300 patients hadreached a primary end point at that time, in which

case the trial could be extended. On March 6, 2004,the board recommended extending the study until

May 2005 without disclosing the reasons. However,since the prespecified criteria had been met, thesteering committee decided to conclude the study

as planned on September 30, 2004,

11

and imple-mented, without knowledge of the results, an exten-

sion phase with death from any cause as the (nom-inal) primary outcome. On February 24, 2005, after

this article had been submitted for publication, the

data and safety monitoring board indicated that themain reasons for its recommendation were interim

analyses showing a trend toward more cardiovas-cular events in the first 10 days after randomization

among patients assigned to cardiac resynchroniza-tion than among those assigned to medical therapy

alone and a trend toward a favorable effect of re-synchronization on long-term mortality that theythought might fail to reach significance by the time

of the planned closure date.

end points

The primary end point was a composite of death

from any cause or an unplanned hospitalization fora major cardiovascular event; only the first event ineach patient was included in this analysis. Data on

patients who underwent elective heart transplanta-tion were censored seven days after the procedure.

Emergency heart transplantation was counted as adeath.

All hospitalizations were adjudicated in a blind-

ed fashion by the end-points committee. The firsthospitalization with documented worsening heartfailure, myocardial infarction, unstable angina, ar-

rhythmia, stroke, or other major cardiovascularevent (e.g., pulmonary embolism or ruptured aortic

aneurysm) or hospitalization owing to or prolongedby a serious procedure-related event (e.g., infection,

pericardial hemorrhage, or tension pneumothorax)was counted in the primary end point. Hospitaliza-

tion with worsening heart failure was defined by theoccurrence of increasing symptoms and the needfor treatment with intravenous diuretics or a sub-

stantial increase in oral diuretics (an increase of atleast 40 mg of furosemide per day, 1 mg of bumet-

anide per day, or 10 mg of torsemide per day) or theinitiation of a combination of a thiazide and a loopdiuretic.

Admissions for symptoms without a document-

ed major cardiac event were not included in theprimary end point, nor were readmissions for leaddisplacement, unless it precipitated a cardiac emer-

gency, or admissions for initial implantation of thedevice, since this was part of the protocol. To pre-

vent bias in favor of cardiac resynchronization, hos-pitalizations within 10 days after randomization ineither group did not count toward the primary end

point.The principal secondary outcome was death

from any cause, which was classified according tomode and cause.

11

Other secondary end points in-

cluded a composite of death from any cause and un-

planned hospitalization with heart failure and, at90 days, the NYHA class and the quality of life as as-

sessed by the patient with the use of the MinnesotaLiving with Heart Failure questionnaire (scores can

range from 0 to 105, with higher scores reflecting apoorer quality of life)

14,15

and the European Quality

of Life5 Dimensions (EuroQoL EQ-5D) instrument(scores can range from 0.594 to 1.000, with lowernumerical values indicating a poorer quality of life;

negative scores are associated with a quality of lifethat is considered worse than death).

16

Death was

given a notional NYHA class of V for the analysis ofchanges in functional class. Several echocardio-

graphic and biochemical variables were assessed incore laboratories, including the severity of cardiacdyssynchrony, ventricular function, mitral regurgi-

tation, and N-terminal probrain natriuretic peptide(Elecsys, Roche Diagnostics), at baseline and at the

3-month and 18-month follow-up visits. Differenc-es from baseline in heart rate and blood pressure





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were also compared in the two groups at follow-

up.

11

No data other than NYHA class were imputedfor patients who died.

statistical analysis

All prespecified analyses were conducted according

to the intention-to-treat principle. P values otherthan for the primary end point are nominal. The

study had a statistical power

17

of 80 percent to iden-tify a 14 percent relative reduction or a 5.7 percent-

age point reduction in the rate of events, given a con-ventional one-sided a

value of 0.025 and a predictednumber of 300 events.

11

The time to an event was

calculated according to the KaplanMeier methodand analyzed with the use of Cox proportional-haz-

ards models, which included baseline NYHA classas a covariate.

18

Continuous data were analyzed

with the use of mixed models, which included base-line variables as patient-level covariates and study

centers as random effects.

19

Dichotomous out-comes were analyzed with the use of nonlinearmixed models, which included the NYHA class as a

patient-level covariate and study centers as randomeffects. The rates of adverse events were compared

between groups by means of Fishers exact test.Analyses were conducted with the use of SAS soft- ware (version 9.12, SAS Institute). The data and

safety monitoring board conducted two planned in-terim analyses with the use of nonsymmetric stop-

ping rules.

20

A total of 404 patients were assigned to receive med-

ical therapy alone and 409 to receive medical therapyplus cardiac resynchronization. The mean duration

of follow-up was 29.4 months (range, 18.0 to 44.7).By the end of the study, the survival status of all pa-

tients was known, 383 patients had reached the pri-mary end point, and 202 patients had died.

study population

Baseline characteristics were similar in the two

groups (Table 1). Patients had well-treated moder-ate or severe heart failure and major left ventricular

systolic dysfunction. Only 43 percent were takinghigh doses of diuretics (defined as at least 80 mg offurosemide, at least 2 mg of bumetanide, or at least

20 mg of torsemide). Beta-blockers were taken atsome time during the study by 85 percent of the pa-

tients in the medical-therapy group and 84 percentof those in the cardiac-resynchronization group.

Implantation of a device was attempted in 404

of the 409 patients assigned to undergo cardiac re-synchronization. One patient died before undergo-ing the procedure, and in four instances, the patient

or investigator decided not to proceed. A cardiac-resynchronization device was implanted and activat-

ed in 390 patients (95 percent), in 349 on the firstattempt; the device was implanted a median of four

days (interquartile range, two to seven) after ran-domization. The median duration of hospitalization

for implantation was five days (interquartile range,two to eight). Before the device could be activated,six patients had an unplanned hospitalization for

cardiovascular reasons that qualified as a primaryend point. Eight patients assigned to undergo car-

diac resynchronization had a device with an addi-tional defibrillator function implanted during thestudy.

In the medical-therapy group, implantation of

a cardiac-resynchronization device alone was at-tempted in 43 patients and implantation of a resyn-chronization device with a defibrillator was attempt-

ed in 23 patients (both approaches were attemptedin 1 patient). The device was activated in 50 patients.

In 10 instances, a device was successfully implantedbut programmed to provide only standard pacemak-er or defibrillator functions to avoid crossover. In

five patients, the attempt at implantation was un-successful. The device was activated in 19 patients

(5 percent) before they reached the primary endpoint. Eight of these patients subsequently reached

a primary end point, six of whom died. Of 31 pa-

tients in whom the device was activated after theyhad reached the primary end point, 7 subsequent-

ly died.

primary end point

By the end of the study, the primary end point had

been reached in 159 patients in the cardiac-resyn-chronization group, as compared with 224 patientswho received medical therapy alone (39 percent vs.

55 percent; hazard ratio, 0.63; 95 percent confi-dence interval, 0.51 to 0.77; P


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* NYHA denotes New York Heart Association, and ACE angiotensin converting enzyme. To convert values for N-terminal probrain natriuretic peptide to picomoles per l iter, divide by 8.457. The area was calculated as the area of the color-flow Doppler regurgitant jet divided by the area of the left atrium in sys-

tole, both in square centimeters. A high-dose loop diuretic consisted of furosemide at a dose of 80 mg or more, bumetanide at a dose of 2 mg or more,

or torsemide at a dose of 20 mg or more.

Table 1. Baseline Characteristics of the Patients.*

CharacteristicMedical Therapy Alone

(N=404)Medical Therapy plus CardiacResynchronization (N=409)

Age (yr)

Median 66 67

Interquartile range 5972 6073

Male sex (%) 293 (73) 304 (74)

NYHA class IV (%) 27 (7) 23 (6)

Dilated cardiomyopathy (%) 193 (48) 177 (43)

Ischemic heart disease (%) 144 (36) 165 (40)

Heart disease of other causes (%) 67 (17) 67 (16)

Heart rate (beats/min)

Median 70 69


Systolic blood pressure (mm Hg)

Median 110 110


Diastolic blood pressure (mm Hg)

Median 70 70Interquartile range 6080 6079

N-terminal probrain natriuretic peptide (pg/ml)

Median 1806 1920


Left ventricular ejection fraction (%)

Median 25 25


Left ventricular end-systolic volume index (ml/m

2

)

Median 117 121


QRS duration (msec)

Median 160 160

Interquartile range 152180 152180Interventricular mechanical delay (msec)

Median 50 49


Mitral-regurgitation area

Median 0.23 0.21

Interquartile range 0.110.34 0.120.33

Glomerular filtration rate (ml/min/1.73 m

2

)

Median 61 60


Use of an ACE inhibitor or angiotensin-receptor blocker (%) 383 (95) 387 (95)

Use of a beta-blocker (%) 298 (74) 288 (70)

Use of spironolactone (%) 238 (59) 219 (54)

Use of a high-dose loop diuretic (%) 177 (44) 175 (43)

Use of digoxin (%) 181 (45) 165 (40)





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had unplanned hospitalizations for a major cardio-vascular event that occurred within 10 days after

randomization and were therefore not counted asprimary end points.

deaths

In the cardiac-resynchronization group, 82 patients

died, as compared with 120 patients who had beenassigned to medical therapy alone (20 percent vs.

30 percent; hazard ratio, 0.64; 95 percent confi-

dence interval, 0.48 to 0.85; P


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echocardiographic, biochemical,

and hemodynamic assessments

At both 3 months and 18 months, the left ventricularejection fraction was significantly greater, the leftventricular end-systolic volume index was signifi-

cantly lower, the area of mitral regurgitation wassignificantly smaller, and the interventricular me-

chanical delay was significantly shorter in the car-diac-resynchronization group than in the medical-

therapy group (Table 3). By 18 months, plasmalevels of N-terminal probrain natriuretic peptide were lower among patients in the cardiac-resyn-

chronization group (Table 3). Systolic blood pres-sure was higher at both 3 months and 18 months

among patients in the cardiac-resynchronizationgroup.

serious adverse events

There was one device-related death in each group:

one patient in the cardiac-resynchronization groupdied of heart failure aggravated by lead displace-ment, and one patient in the medical-therapy group

died of septicemia after receiving a device. Themost common adverse device- or procedure-related

events in the cardiac-resynchronization group werelead displacement (24 patients), coronary-sinus dis-

section (10 patients), pocket erosion (8 patients),pneumothorax (6 patients), and device-related in-fection (3 patients). Worsening heart failure was

more common in the medical-therapy group (affect-ing 263 patients, as compared with 191 patients

in the cardiac-resynchronization group; P


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mon in the cardiac-resynchronization group (af-

fecting 64 patients in that group, as compared with41 in the medical-therapy group; P=0.02). The fre-quencies of respiratory tract infections, hypoten-

sion, falls or syncope, acute coronary syndromes,renal dysfunction, ventricular arrhythmias or ecto-

py, and neurologic events were similar in the twogroups.

We found that cardiac resynchronization substan-tially reduced the risk of complications and death

among patients with moderate or severe heart fail-ure owing to left ventricular systolic dysfunction and

cardiac dyssynchrony. The benefits were similaramong patients with ischemic heart disease and pa-

tients without ischemic heart disease and were inaddition to those afforded by pharmacologic thera-

py. The data are consistent with a resynchronization-induced reduction in cardiac dyssynchrony, leadingto a sustained increase in left ventricular perfor-

mance and a diminution of mitral regurgitation and,in turn, a rise in perfusion pressure, a fall in cardiac

filling pressure, and favorable left ventricular re-modeling. These changes in function translate intoimprovements in well-being and decreases in symp-

toms, complications, and the risk of death.The favorable effects of cardiac resynchroniza-

tion on symptoms, the quality of life, ventricularfunction, and blood pressure in our trial are similar

to those reported in previous trials.

4-8

However, we

also found that cardiac resynchronization signifi-cantly reduced the risk of death. Calculations based

on hazard ratios suggest that, for every nine devic-es implanted, one death and three hospitalizations

for major cardiovascular events are prevented. Thiseffect is in addition to the benefits of pharmacolog-

ic therapy and is similar to the reduction in the riskof death associated with beta-blocker therapy ascompared with placebo in a similar population.

21

The benefit of cardiac resynchronization therapyin our study was due, at least in part, to the adher-

ence of patients and investigators to the protocoland to the increasing effect of cardiac resynchroni-

zation over a long follow-up period, but it was notdue to the recruitment of patients at higher risk forevents than those in other studies. Indeed, the mor-

tality rate was lower than that in many other studies,possibly reflecting the high standard of care, the

presence of less severe heart failure, or both.

22-24

The extent to which risk can be modified may begreater among patients with less severe disease.

Cardiac resynchronization may be beneficial in pa-tients with cardiac dyssynchrony even if their symp-toms are not severe, although we excluded patients

judged by the investigator to be in NYHA class I or II.The hazard ratio for death among patients with a

cardiac-resynchronization device, as compared withthose receiving medical therapy alone (0.64; 95 per-cent confidence interval, 0.48 to 0.85; P


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0.2 0.5 1.0 2.0

Medical Therapy Better

Resynchronization Better

NYHA class

66.4 yr

Sex

Overall

Male

Female

Age


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owing either to the cause of the arrhythmia or tothe effects of the shock.

27

Assuming that the com-

bination of a cardiac-resynchronization device anda defibrillator could prevent two thirds of sudden

deaths, a future study would require 1300 patientsper group and a follow-up period similar to ours tohave a statistical power of 90 percent to detect an ab-

solute reduction in the risk of death from any causeof 5 percent with the use of combination therapy,

as compared with the use of cardiac resynchroniza-

tion alone.In summary, we found that cardiac resynchroni-

zation is an effective therapy for patients with left

ventricular systolic dysfunction and cardiac dyssyn-chrony who have moderate or severe heart failureand who are in sinus rhythm.

Supported by a grant from Medtronic.Dr. Cleland reports having served as a consultant for Medtronic,

Amgen, Menarini, and Pfizer and having received speakers hono-raria from Medtronic, Takeda, AstraZeneca, and Pfizer and grantsupport from the Medical Research Council (United Kingdom),

Hull and East Yorkshire Cardiac Trust, Medtronic, Vasomedical, andAbbott. Dr. Daubert reports having served as a consultant for andhaving received speakers honoraria from Medtronic and St. JudeMedical. Dr. Erdmann reports having served as a consultant for andhaving received speakers honoraria from Takeda, Merck (Darm-stadt), Medtronic, and Guidant. Dr. Freemantle reports havingserved as a consultant for Medtronic and Pfizer and having receivedspeakers honoraria from Medtronic and grant support fromMedtronic, Aventis, Amgen (United Kingdom), and the BritishHeart Foundation. Dr. Gras reports having served as a consultant forand having received speakers honoraria from Medtronic andGuidant. Dr. Kappenberger reports having served as a consultantfor Medtronic, having received speakers honoraria from Medtron-

ic, Biotronik, and Guidant, and having received grant support fromMedtronic and the Swiss National Foundation for Scientific Re-search, Commission for Technology and Innovation/Kommissionfr Technologie und Innovation, and the Swiss Heart Foundation.Dr. Tavazzi reports having served as a consultant for Medtronic, Me-narini, Servier, and Pfizer and having received speakers honorariafrom Medtronic, Novartis, and Takeda.

This article is dedicated to the memory of Werner Klein, profes-sor of cardiology at the University Hospital of Graz (Austria), amember of the steering committee who died in 2004. He contribut-ed substantially to the design and conduct of the study but did notlive to see it completed. His wise counsel is greatly missed by his col-leagues.

appendix

The following persons participated in the CARE-HF Study:

Steering Committee

J.G.F. Cleland (chair), J.-C. Daubert, E. Erdmann, D.

Gras, L. Kappenberger, W. Klein, L. Tavazzi; Data and Safety Monitoring Board P.A. Poole-Wilson, L. Rydn (chair), H. Wedel, H.J.J.Wellens; End-Points Committee B. Uretsky, K. Thygesen; Independent Device-Related Adverse-Event Assessor

D. Bcker; StudyManagement M.M.H. Marijianowski; Statistical Analysis

N. Freemantle, M.J. Calvert; Pharmacologic Vigilance and Data Manage-ment

Quintiles; Investigators

Austria

: G. Christ, F. Fruhwald, R. Hofmann, A. Krypta, F. Leisch, R. Pacher, F. Rauscha; Belgium

: R. Tav-ernier; Denmark

: P.E. Bloch Thomsen, S. Boesgaard, H. Eiskjr, G.T. Esperen, J. Haarbo, A. Hagemann, E. Korup, M. Mller, P. Mortensen,P. Sgaard, T. Vesterlund; Finland

: H. Huikuri, K.I. Niemel, L. Toivonen; France

: F. Bauer, A. Cohen-Solal, C. Crocq, P. Djiane, J.L. Dubois-Rande, P. de Groote, Y. Juilliere, G. Kirkorian, M. Komajda, T. Laperche, H. Le Marec, C. Leclercq, C. Tribouilloy; Germany

: F. Er, E. Fleck,U.C. Hoppe, F.X. Kleber, B. Maisch, J. Neuzner, C. Reithmann, T. Remp, C. Schmitt, C. Stahl, R.H. Strasser; Italy

: M.C. Albanese, A. Bar-toloni, M. Bocchiardo, A. Capucci, A. Carboni, A. Circo, M. Disertori, R. del Medico, T. Forzani, M. Frigerio, A. Gavazzi, M. Landolina, M.

* Differences were not adjusted for the higher mortality rate in the medical-therapy group. A plus sign indicates a greatervalue, and a minus sign a smaller value, in the cardiac-resynchronization group than in the medical-therapy group. CI de-notes confidence interval.

The area was calculated as the area of the color-flow Doppler regurgitant jet divided by the area of the left atrium in sys-tole, both in square centimeters.

To convert the values for N-terminal probrain natriuretic peptide to picomoles per liter, divide by 8.457.

Table 3. Hemodynamic, Echocardiographic, and Biochemical Assessments.*

VariableDifference in Means

at 3 Mo (95% CI) P ValueDifference in Meansat 18 Mo (95% CI) P Value

Heart rate (beats/min) +1.1 (1.2 to 3.4) 0.33 +1.0 (1.5 to 3.6) 0.43

Systolic blood pressure (mm Hg) +5.8 (3.5 to 8.2)


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Lunati, S. Mangiameli, M. Piacenti, A. Pit, P.A. Ravazzi, A. Raviele, M. Santini, A. Serio, G.P. Trevi, M. Volterrani, M. Zardini; the Netherlands

:F.A.L.E. Bracke, C.C. de Cock, A. Meijer, R. Tukkie; Spain

: J. Casares Mediavilla, M. Concha, J.F. Delgado, A. Gonzlez-Garca, R. Muoz-Aguilera, J. Martnez Ferrer, F. Ridocci; Sweden

: B. Andren, J. Brandt, P. Blomstrm, M. Edner, K. Hellstrm, S. Jensen, B. Kristensson, F. Ma-ru, S.J. Moller, F. Rnn, P. Smedgrd, G. Wikstrm; Switzerland

: J. Fuhrer, G. Girod; United Kingdom:

G.H. Broomes, S. Chalil , H. Dargie, W.Davies, A. Delaney, P. Elliott, G.K. Goode, G. Haywood, G.C. Kaye, A.S. Kurbaan, R. Lane, T. Levy, F. Leyva, H. Marshall, S. Muhyaldeen, N.Nitikin, M.J.D. Roberts, J.D. Skehan, W.D. Toff, D.J. Wright; Core Echocardiography Laboratory

(

Pavia, Italy)

C. Bassi, S. Ghio, E. Ghiz-zardi, G. Magrini, M. Pasotti, V. Pierota, E. Tellaroli, A. Serio, L. Scelsi; Core

Neuroendocrine Laboratory (Graz, Austria)

A. Fahrleitner,G. Leb, H. Wenisch

; Therapy Delivery (

Kingston-upon-Hull

, United Kingdom)

A. Bennett, M. Cooklin, J. Ghosh, S. Hurren, G.C. Kaye,N.K. Khan.

references

1.

Khand A, Gemmel I, Clark AL, Cleland JGF. Is the prognosis of heart failure im-proving? J Am Coll Cardiol 2000;36:2284-6.

2.

Cleland JGF, Clark AL. Delivering thecumulative benefits of triple therapy to im-prove outcomes in heart failure: too manycooks will spoil the broth. J Am Coll Cardiol2003;42:1234-7.

3.

Rogers JG, Cain ME. Electromechanicalassociations. N Engl J Med 2004;350:2193-5.

4.

Cazeau S, Leclercq C, Lavergne T, et al.Effects of multisite biventricular pacing inpatients with heart failure and intraventricu-lar conduction delay. N Engl J Med 2001;

344:873-80.

5.

Young JB, Abraham WT, Smith AL, et al.Combined cardiac resynchronization andimplantable cardioversion defibrillation inadvanced chronic heart failure: the MIRACLEICD Trial. JAMA 2003;289:2685-94.

6. Abraham WT, Fisher WG, Smith AL, et al.Cardiac resynchronization in chronic heartfailure. N Engl J Med 2002;346:1845-53.7. Higgins SL, Hummel JD, Niazi IK, et al.Cardiac resynchronization therapy for thetreatment of heart failure in patients with in-traventricular conduction delay and malig-nant ventricular tachyarrhythmias. J AmColl Cardiol 2003;42:1454-9.8. Bristow MR, Saxon LA, Boehmer J, et al.Cardiac-resynchronization therapy with or

without an implantable defibrillator in ad-vanced chronic heart failure. N Engl J Med2004;350:2140-50.9. McAlister FA, Ezekowitz JA, Wiebe N, etal. Systematic review: cardiac resynchroni-zation in patients with symptomatic heartfailure. Ann Intern Med 2004;141:381-90.[Erratum, Ann Intern Med 2005;142:311.]

10. Calvert M, Freemantle N, Cleland JG.Cardiac resynchronization therapy in heartfailure. Ann Intern Med 2005;142:305-7.11. Cleland JGF, Daubert JC, Erdmann E, etal. The CARE-HF study (Cardiac Resynchro-nisation in Heart Failure study): rationale,design and end-points. Eur J Heart Fail2001;3:481-9.12. Calvert MJ, Freemantle N, Cleland JGF.The impact of chronic heart failure onhealth-related quality of life data acquired inthe baseline phase of the CARE-HF study.Eur J Heart Fail 2005;7:243-51.13. Cleland JGF, Daubert JC, Erdmann E, et

al. Baseline characteristics of patients re-cruited into the CARE-HF study. Eur J HeartFail 2005;7:205-14.14. Rector TS, Tschumperlin LK, Kubo SH,et al. Use of the Living With Heart Failurequestionnaire to ascertain patients per-spectives on improvement in quality of life

versus risk of drug-induced death. J CardFail 1995;1:201-6.15. Rector TS, Kubo SH, Cohn JN. Validityof the Minnesota Living with Heart Failurequestionnaire as a measure of therapeuticresponse to enalapril or placebo. Am J Car-diol 1993;71:1106-7.16. Brooks R. EuroQol: the current state ofplay. Health Policy 1996;37:53-72.17. Shih JH. Sample size calculation for

complex clinical trials with survival end-points. Control Clin Trials 1995;16:395-407.18. Collett D. Modelling survival data inmedical research. London: Chapman & Hall,1994.19. McCulloch CE, Searle SR. Generalized,linear, and mixed models. New York: JohnWiley, 2001.

20. Lan KKG, DeMets DL. Discrete sequen-tial boundaries for clinical trials. Biometrika1983;70:659-63.21. CIBIS-II Investigators and Committee.The Cardiac Insufficiency Bisoprolol StudyII (CIBIS-II): a randomised trial. Lancet1999;353:9-13.22. Packer M, Coats AJS, Fowler MB, et al.Effect of carvedilol on survival in severechronic heart failure. N Engl J Med 2001;344:1651-8.23. The CONSENSUS Trial Study Group.Effects of enalapril on mortality in severecongestive heart failure: results of the Coop-

erative North Scandinavian Enalapril Surviv-al Study (CONSENSUS). N Engl J Med 1987;316:1429-35.24. Pitt B, Zannad F, Remme WJ, et al. Theeffect of spironolactone on morbidity andmortality in patients with severe heart fail-ure. N Engl J Med 1999;341:709-17.25. Bardy GH, Lee KL, Mark DB, et al.Amiodarone or an implantable cardiovert-erdefibrillator for congestive heart failure.N Engl J Med 2005;352:225-37.26. Cleland JGF, Ghosh J, Freemantle N, etal. Clinical trials update and cumulativemeta-analyses from the American College ofCardiology: WATCH, SCD-HeFT, DINAMIT,CASINO, INSPIRE, STRATUS-US, RIO-Lip-ids and cardiac resynchronisation therapy in

heart failure. Eur J Heart Fail 2004;6:501-8.27. Moss AJ, Greenberg H, Case RB, et al.Long-term clinical course of patients aftertermination of ventricular tachyarrhythmiaby an implanted defibrillator. Circulation2004;110:3760-5.Copyright 2005 Massachusetts Medical Society.


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