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(Circulation. 2000;101:378.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Effects of Metoprolol CR in Patients With Ischemic and Dilated Cardiomyopathy
The Randomized Evaluation of Strategies for Left Ventricular Dysfunction Pilot Study
Correspondence to Project Office, Canadian Cardiovascular Collaboration, 2nd Floor, McMaster Clinic, 237 Barton St E, Hamilton, Ontario L8L 2X2, Canada.
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Abstract |
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Background—Metoprolol provides clinical benefits in patients with congestive heart failure (CHF). In this study, we investigated the effects of controlled-release metoprolol (metoprolol CR) on clinical status, on left ventricular (LV) volumes and function, and on neurohumoral activation in a large number of patients with CHF of mixed causes.
Methods and Results—Four hundred twenty-six patients with symptomatic CHF were randomized to receive metoprolol CR or placebo for 24 weeks. Metoprolol CR did not affect 6-minute walk distance, New York Heart Association functional class, or quality of life. However, there was a significant improvement in measures of LV function with an attenuation in the increase in LV end-diastolic (+23±65 mL [placebo] versus +6±61 mL, P=0.01) and LV end-systolic (+19±55 mL [placebo] versus -2±51 mL, P<0.001) volumes after 24 weeks of therapy. LV ejection fraction was unchanged (-0.05% or -0.005) in the placebo group but increased by 2.4% in the metoprolol CR–treated patients (P=0.001). Patients receiving metoprolol CR had a greater decrease in angiotensin II (P=0.036) and renin (P=0.032) levels but an increase in N-terminal atrial natriuretic peptide and brain natriuretic peptide levels (P<0.01). There were fewer deaths in the group receiving ß-blockers (3.4% versus 8.1%), and there was a similar number of patients experiencing the composite outcomes of death or any hospitalization.
Conclusions—When added to ACE inhibitors, angiotensin II receptor antagonists, or both, the use of metoprolol CR improves ventricular function, reduces activation of the renin-angiotensin systems, and results in fewer deaths.
Key Words: heart failure • receptors, adrenergic, beta • hormones • ventricles
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Introduction |
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Additional clinical benefits are provided by ß-adrenergic blockers when administered in addition to ACE inhibitors.1 2 3 4 5 6 7 8 9 The recently presented Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) reported a significant beneficial effect of metoprolol CR on survival rates in patients with congestive heart failure (CHF) caused by both idiopathic dilated cardiomyopathy (IDC) and ischemic cardiomyopathy. However, only 1 small study evaluated the effects of metoprolol on left ventricular (LV) volumes and function in patients with chronic ischemic cardiomyopathy,10 and an extensive assessment of neurohormones has not been performed in any large trial of the use of metoprolol in patients with CHF of mixed causes.
The Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) Pilot Study represents one of the largest studies conducted of the use of metoprolol in patients with CHF of mixed causes who were receiving either angiotensin receptor blockers (ARBs), ACE inhibitors, or a combination. The objectives of stage II of the RESOLVD Pilot Study were to comprehensively evaluate the effects of the administration of metoprolol CR in addition to candesartan, enalapril, or the combination of candesartan and enalapril on tolerability, 6-minute walk distance, ventricular volumes and function, neurohumoral parameters, quality of life, and New York Heart Association (NYHA) functional class in a broad population of patients with CHF that included individuals with either ischemic or nonischemic cardiomyopathy.
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Methods |
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The RESOLVD Pilot Study was a randomized double-blinded trial of various therapeutic options in patients with CHF that consisted of a 3x2 partial factorial design with a 2-stage randomization. In stage I, patients were randomized to receive candesartan at 1 of 3 dosage levels (4, 8, or 16 mg/d), 20 mg/d enalapril, or the combination of candesartan (4 or 8 mg) and enalapril (20 mg) for a period of 17 weeks. In stage II, eligible patients were randomized to receive 200 mg/d metoprolol CR or placebo and followed for an additional 24 weeks.11
To be eligible for entry into the RESOLVD Pilot Study, patients had to have symptomatic CHF (NYHA II to IV), a 6-minute walk distance of <500 m, and an LV ejection fraction (EF) of <40%. Patients with chronic heart failure from any cause were allowed in the trial. The cause of heart failure was determined by the investigators based on clinical judgment. The primary objective of stage II of the RESOLVD Pilot Study was to determine the efficacy and safety of the administration of the new controlled-release formulation of metoprolol (metoprolol CR) in addition to the stage I study medication in terms of 6-minute walk distance and neurohumoral parameters. The primary safety end point was a combination of adverse events (defined as symptomatic hypotension, worsening of CHF, and symptomatic bradycardia) and tolerability (proportion of patients who did or did not reach their assigned target dose, plus those who discontinued their assigned treatment). The secondary objectives were to determine the effects of the combination of metoprolol CR with stage I medications on ventricular volumes and function, NYHA functional class, and quality of life. All patients signed informed consent, and the protocol was approved by the ethics committees of all of the investigators involved in the study.
At the end of stage I (week 17), all patients eligible for stage II received 12.5 mg metoprolol CR once daily for 1 week (run-in period). If they tolerated this dose, the patients were randomized to receive either 25 mg metoprolol CR once daily or placebo. The dose of metoprolol was increased gradually every 2 weeks to a maximum dosage of 200 mg metoprolol CR daily in the following steps: 50, 75, 100, and 200 mg/d. Dosage reduction or delayed up-titration of metoprolol CR was allowed at any time. The total follow-up from the time of randomization into stage II until the end of the study was 24 weeks. Heart rate, blood pressure, biochemical and neurohumoral parameters, 6-minute walk distance, quality of life (assessed with the use of the Minnesota Living With Heart Failure questionnaire), NYHA functional class, and quantitative radionuclide ventriculography were obtained during the week before the run-in period (end of stage I) and at the end of the study.
Neurohumoral Analyses
Blood samples were drawn after an overnight fast and 30 minutes
of rest in the supine position. Norepinephrine,
epinephrine, and dopamine were measured with HPLC, whereas
angiotensin II, aldosterone, and endothelin I
were measured with radioimmunoassay.12 13 Both N-terminal
proatrial natriuretic peptide (pro-ANP) and brain
natriuretic peptide (BNP) were measured in Oslo, Norway,
with the use of previously reported techniques.14 15 The
neurohumoral data for our study population were compared with those for
aged-matched healthy volunteers without cardiac disease, from whom
blood samples were taken at 1 Italian center and 4 Canadian
centers.
Statistical Analyses
All analyses were performed on an intention-to-treat
basis. ANOVA was used to examine the efficacy of the administration of
metoprolol CR in addition to candesartan/enalapril on exercise
tolerance, ventricular function, neurohormonal
parameters, systolic and diastolic
blood pressures, and resting heart rate. Clinical events, NYHA
functional class, and quality of life were analyzed using the
Mantel-Haenszel test. Data not distributed normally (eg, for
neurohormones) were log transformed before statistical comparisons were
made. All data are presented as mean±SD.
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Results |
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Baseline Demographics and Patient Characteristics
Of the 768 patients randomized to stage I of the study, 426 were randomized to stage II. Four hundred sixty-eight patients were entered in the run-in period, but 52 (11%) were not randomized because of poor adherence (n=7), patient refusal (n=4), adverse events (n=24; 5%), and other exclusion reasons (n=17). Of the 24 patients who developed adverse events and were not randomized into stage II, 7 patients experienced symptoms and signs of worsening heart failure, 10 patients complained of nonspecific cardiac or respiratory symptoms, 4 patients presented with abdominal or chest discomfort, 1 patient died suddenly, and 2 patients were not randomized due to unknown reasons. The remaining 426 patients were randomized to receive metoprolol CR or to placebo. Three hundred forty-two patients randomized in stage I were not offered randomization into stage II because of contraindication to ß-blocker, ongoing treatment with ß-blockers, or unwillingness to pursue the second stage of the trial. The 342 patients in stage I who were not offered randomization into stage II were continually followed up at 8-week intervals. End point assessments were also made and collected. Because of the early termination of the study, 29 (7%) patients were treated for <24 weeks, and their duration of follow-up was slightly reduced by a mean of 11±6 days. For these patients, end point assessments were made at the time of termination.
The clinical characteristics of patients randomized into stage II are
presented in Table 1
.
There were no significant differences between the 2 groups. The
percentage of patients receiving the target dose of ACE
inhibitors, candesartan, or both was 
85% at the time of
randomization into phase II, with the highest group being the group
treated with candesartan or enalapril alone (91% to 95%) and the
lowest being the group treated with high-dose enalapril and candesartan
(85%).
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Six-Minute Walk Distance and Neurohumoral Parameters
Long-term administration of metoprolol CR did not cause any change
in the 6-minute distance walked (metoprolol CR 398±84 to 397±95 m,
placebo 399±85 to 396±102 m). This was also true for the group
treated with candesartan alone (-4.8±64 m), enalapril alone
(-7.6±57.6 m), or the combination of enalapril and candesartan
(-1.9±58 m). In addition, these were no significant changes when only
patients with lower exercise capacity (<400 m) were considered
(metoprolol CR 332±61 to 342±81 m, placebo 325±52 to 321±64 m;
NS).
The effects of metoprolol on neurohumoral activation are
presented in Table 2. Metoprolol
CR provided an additional reduction in plasma renin and
angiotensin II levels but did not decrease the other
neurohormones. Renin and angiotensin II levels decreased to
a similar extent in patients receiving candesartan alone or the
combination of candesartan plus enalapril before the administration of
metoprolol. Metoprolol CR–treated patients exhibited a significant
increase in both N-terminal ANP and BNP.
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Tolerability and Clinical Events
Metoprolol CR was as well tolerated as placebo at all titration
visits, with an overall discontinuation rate of 11% for patients
treated with metoprolol versus 12% for those treated with placebo. The
mean dose of metoprolol was 156±70 mg, and 81% of patients were
receiving the maximal dose of metoprolol CR (200 mg/d). The mean time
to maximum titration was 93 days for the metoprolol group versus 85
days for the placebo group (P<0.05). The overall compliance
was excellent, with only 7% of patients who were randomized to receive
metoprolol CR taking <80% of their study medication, a rate similar
to that for placebo (8%).
The tolerability and events related to metoprolol CR and placebo are
presented in Table 3. Patients
receiving metoprolol CR had a trend toward fewer deaths (n=8, 3.7%)
compared with placebo (n=17, 8.1%). Sixteen patients died suddenly
without worsening CHF (metoprolol n=6, placebo n=10), and 4 patients
died suddenly with worsening CHF (metoprolol n=1, placebo n=3). Other
causes of death included stroke (n=2), cancer (n=2), and myocardial
infarction (n=1). The numbers of patients hospitalized or reporting any
serious adverse event were similar in the metoprolol CR and placebo
groups. There was an increase in hospitalization rates for CHF in
metoprolol CR–treated patients (n=15 [7.9%] versus n=5 [3.3%],
95% CI 1.01 to 5.63) that peaked at 120 days. The hospitalized
patients treated with metoprolol CR exhibited similar clinical
characteristics and LV volumes and function at baseline as the other
patients. However, prerandomization angiotensin II levels
were significantly higher in patients who developed CHF while treated
with metoprolol (55.3±33.2 [CHF] versus 33.2+25 pg/mL [non-CHF],
P<0.001). The number and profile of nonserious adverse
events, as well as the causes for the discontinuation of study
medication, were similar in the 2 groups.
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Quality of Life, Functional Class, and Hemodynamic
and Cardiac Effects
Metoprolol CR caused no significant change in the quality of life
score or in NYHA functional class. Therapy with metoprolol CR caused no
significant change in systolic or diastolic blood
pressure at the initiation of therapy or during the course of the
study. Metoprolol CR caused a decrease in heart rate of 
6 to 8 bpm
once maximal doses were achieved. The changes in blood pressure and
heart rate were similar regardless of whether patients received
candesartan, enalapril, or the combination before randomization into
phase II.
The effects of metoprolol and placebo on cardiac volume and
function are presented in the Figure and Table 4. Patients receiving placebo had no
change in EF but exhibited a significant increase in systolic
and diastolic ventricular volumes. In contrast,
24 weeks of treatment with metoprolol CR significantly increased LVEF
and prevented the increase in end-systolic and
end-diastolic volumes. The effects of metoprolol on LV
function and volumes were significant and of similar magnitude in the
ischemic and nonischemic groups.
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). Data are mean±SEM.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendixReferences |
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Stage II of the RESOLVD Pilot Study is one of the largest published randomized study of the use of metoprolol in patients with CHF. The administration of metoprolol improved LV function and prevented LV dilatation but did not result in significant improvements in symptoms, 6-minute walk distance, or quality of life. In addition, despite the use of an ACE inhibitor, ARB, or the combination in stage I, metoprolol CR resulted in a further suppression of renin and angiotensin II levels.
The CR formulation of metoprolol16 was used in patients
with CHF of mixed causes. Compared with the conventional metoprolol
tablet, the CR formulation has 30% less
bioavailability17 ; however, a dose of 200 mg of the CR
formulation caused more pronounced ß-blockade than 150 mg of the
immediate-release formulation in patients with heart failure.
Metoprolol CR caused the expected decrease in heart rate but no
significant changes in systolic or diastolic blood
pressure. These findings are consistent with previous studies
showing no change in blood pressure after the first month of the
initiation of metoprolol.2 18 19 Despite a mean daily dose
of 160 mg metoprolol, heart rate decreased by only 6 bpm by the end of
the titration phase. This moderate decrease in heart rate is less
striking than previously reported with the use of metoprolol in
patients with more severe CHF caused by dilated
cardiomyopathy.2 19 However, the
magnitude of decrease in heart rate reported in this study is similar
to the 6.8-bpm decrease obtained with carvedilol in the Australia/New
Zealand Trial, which is a study of patients with less severe heart
failure and ischemic
cardiomyopathy.6
The administration of metoprolol CR produced a significant 0.024 improvement in LVEF after an average of 6 months of therapy compared with no change (-0.05) in patients treated with a placebo. The increase in LVEF is slightly less than that reported in other studies of the use of metoprolol and other ß-blockers but more than that reported by Woodley et al20 on the use of bucindolol in patients with ischemic heart failure. The reasons for this are not clear, but because of the small sample size in many of these trials, it is difficult to make conclusions regarding a lesser effect on EF in the present study population of patients with CHF for which the cause is in large part ischemic cardiomyopathy. In addition to its significant effect on EF, metoprolol CR prevented the increase in LV end-diastolic and end-systolic volumes. These observations are in agreement with those of Hall et al,18 who reported a favorable effect on LV volumes after 3 months of therapy with metoprolol in patients with CHF caused by IDC. Similar decreases in volumes have been reported in the Australia/New Zealand Trial6 and with the use of bucindolol in patients with ischemic heart failure.20 Accordingly, our data extend the available data on the beneficial effect of metoprolol on LV geometry from a population with IDC to a population with heart failure largely caused by ischemic heart disease.
Metoprolol CR produced no change in NYHA functional class, quality of life, or 6-minute walk distance. These results are consistent with the heterogenous results reported in various randomized trials, with some trials reporting a favorable effect,10 some reporting positive effects but after a longer duration of treatment,2 8 21 and others reporting no sustained benefit.6 The reason for the absence of consistent improvement in submaximal exercise capacity with the use of a ß-blocker is likely multifactorial, but it is possible that the short follow-up period may have played a role in the lack of exercise effect. In addition, the SD for the 6-minute walk test in this trial was 84 m, as opposed to the expected 39 m used for sample size calculation.11 Such discrepancy likely contributed to a lack of power to detect differences between the 2 treatment arms.
In this study, metoprolol therapy caused no significant change in plasma catecholamine levels but did cause a decrease in renin levels, which is in agreement with previous reports.18 22 23 A decrease in angiotensin II levels by the use of a ß-blocker has been reported in normotensive and hypertensive subjects but not in patients with CHF.24 In fact, the magnitude of suppression of angiotensin II by the short-term use of nonselective or selective ß-adrenergic blockers appears to be comparable to the suppression provided by an ACE inhibitor. Thus, our data confirm the efficacy of ß-adrenergic blockade to decrease renin activity and angiotensin II levels when administered on a long-term basis in patients with CHF who have already been treated with an ACE inhibitor or an ARB. Nevertheless, the absence of a decrease in aldosterone levels emphasizes the multifactorial control of aldosterone secretion in patients with CHF. The metoprolol CR–treated group experienced an increase in N-terminal ANP and BNP levels at 6 months. There are little data available regarding the effect of ß-blockers on natriuretic peptide levels in CHF patients; however, a recent population-based survey reported that the long-term administration of ß-blocking agents increases circulating levels of ANP and BNP.25 The reasons for such an increase are not readily apparent. One possibility is that metoprolol-increased LV filling pressure is an effect that would be consistent with the increased incidence of hospitalization for patients with worsening heart failure with the use of metoprolol found in this relatively short trial. Alternatively, ß-adrenergic blockade may decrease the excretion of natriuretic peptides or directly block the inhibitory effect of adrenergic activation on natriuretic peptides and result in a compensatory beneficial increase in natriuretic peptides.
Neither arm of the RESOLVD Pilot Study was powered to detect differences in clinical end points such as death. However, despite a short follow-up duration, treatment with metoprolol CR appears to be associated with a reduction in mortality rates. In fact, the proportion of reduction in all-cause mortality, sudden death, and pump failure death can be superimposed on those recently reported in MERIT-HF.9 Interestingly, cause-specific analysis of hospitalizations showed an increase in the diagnosis of hospitalizations for CHF in the metoprolol CR group but a concomitant decrease in hospitalizations for reasons other than CHF, leading to a neutral effect on all-cause hospitalizations. The reasons for the more common hospitalizations for CHF in the metoprolol CR group may be related to the vigorous titration regimen used in this trial. Although a similar mean dosage (159 mg/d metoprolol CR) was reported in MERIT-HF,9 such a dosage is higher than that (87 mg/d metoprolol) used by Fisher et al10 in patients with ischemic heart failure10 and the dosage (106 mg/d metoprolol) used in the Metoprolol in Dilated Cardiomyopathy Trial.2 Nevertheless, most patients who worsened while receiving metoprolol were successfully managed with a lowered dose of ß-blocker, which explains why, as reported in MERIT-HF,9 no difference was observed in the percentage of patients who stopped receiving the blinded medication.
In summary, treatment with metoprolol CR for 6 months in patients
with moderately severe CHF is well tolerated and improves LV function
and some of the neurohormonal profile, regardless of the cause of CHF.
The trend toward fewer deaths in this study was supported by the
results of the recently presented MERIT-HF Trial.
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Appendix |
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Investigators and Committee Members
Clinical Centers
Brazil: W. Cirillo, R. Decanini, O. Rizzi Coelho,* Á. Avezum,* M.S. Pacheco Peixoto, L.S. Piegas, J.M. Rossi Neto, M. Paiva, A.C. Carvalho,* D.R. de Almeida, I.M. Ligori Fernandes, M.C. Malavasi, R. Pavanello,* M. Canesin, S. Ishii, and A.C. Pereira Barretto.*
Canada: J. Imrie, R. Moore, K. Woo,* V. Bernstein,* H.F. Mizgala, S. Mooney, D. Hilbich, R. Kuritzky, D.W. Rupka,* M.M. Blackwell, L. Breakwell, J.M. Kornder, S.A. Pearce, P. Polasek,* P.M. Richardson, J. Grant, D. Isaac,* P. Beresford, P. Giannoccaro, D. Roth,* P. Greenwood,* T. Muzyka, A. Prosser, N. Brass, W. Hui,* L. Kvill, M. Goeres, K. MacDonald, M. Senaratne,* L. Hill, D. Humen,* K.K. Teo, N. Habib,* Mrs N. Habib, S. Teekasingh, J. MacKenzie, B. McEwen, A. Morris,* A. Dhair, C. Lai,* K. Kwiatkowski, J. Brugos, S. Nawaz,* J. Andrews, G. Moe,* K. Freskiw, B. Gilbert, C.D. Morgan,* B. Bozek, F. Halperin, A.J. Ricci,* N. Singh, G. Cappelli, T. Boyne,* E. Fallen, A. Panju,* G. Woodcock, E. Kent, A.D. Kitching,* H. Sullivan, D. Tomson, R.S. McKelvie,* R.T. Tsuyuki, S. Yusuf, Y.K. Chan,* D. Thomson, J.M.O. Arnold,* G. Hurwitz, R. Miles, A. Baker, A. Haspect, S. Smith,* J. Bedard,* L. Lavoie, L. Dufort, R. Harvey, S. Lepage,* E. Elstein, D. Fitchett,* A. Serpa, L. Day, N. Racine, D. Savard, F. Sestier,* G. Gosselin, J.L. Rouleau, M. White,* L. Whittom, G. Kiwan, S.M. Kouz,* M. Laforest, H. Ouimet, P. Carmichael, J. Lenis,* P. Auger,* F. Grondin, D. Saulnier, J. Campeau, R. Dupuis,* C. Lauzon, M. Genest, N.M. Robitaille,* J. Beaudoin, N. Belanger, G. Houde, P. Talbot,* J. Cossett, C. Koilpillai,* W.J. Sheridan, M. Tobin, and B. Sussex.*
Italy: G. Ascoli, A. Fraticelli, E. Paciaroni,* Como, CO: R. Belluschi,* F. Ruffa, F. Tettamanti, F. Cobelli,* F. Salvucci, R. Arpesella, C. Campana, A. Gavazzi,* V. Cirrincione,* F. Ingrilli, E. Sciortino, A. Boccanelli,* G. Cacciatore, M. Menichelli, E. Bosimini, P. Giannuzzi,* C. Marcassa, M. Porcu, S. Salis, A. Sanna,* G. Comerio, E. Gronda,* and M. Mangiavacchi.
Switzerland: T. Moccetti,* E. Pasotti, and F. Sessa.
United States: W.C. Levy, J. Probstfield,* J. Thompson, M. Gramberg, J. Grover,* D. Towery, K. Ogunyankin, B.N. Singh,* J. Celano, S. Graham, R.M. Kohn,* P. Pande,* A. Sass, R.S. Wiener, S. Rydzinski, R.C. Starling, J. Young,* L. Hays, A. Naftilan,* A. Miller,* A. Varga, and R. Wofford.
Regional Monitors
S. Barnhill, R. de Paula Brito, L. Harris, A. Haspect, T.
Cristina, M. Jarosz, J. Kellen, C. Kingry, R. Letterer, D. La Forge, C.
Liuni, J. MacKenzie, A. Magi, K. Stevens, and P. Squires.
Steering Committee
S. Yusuf (chair); J.L. Rouleau (cochair); A. Maggioni (cochair);
J.M.O. Arnold, Á. Avezum, R. Burns, J. Floras, A. Gavazzi, P.
Held, Å. Hjalmarson, D. Isaac, R. Latini, E. Lindgren, R.S. McKelvie,
L.S. Piegas, D. Pericak, J. Pogue, J. Probstfield, S. Smith, K.
Swedberg, K.K. Teo, R.T. Tsuyuki, C. Vint-Reed, Y. Wang, M. White, E.M.
Wiecek, and J. Young.
External Safety and Efficacy Monitoring Committee
D. Johnstone (chair); P.W. Armstrong; M. Packer, and H.
Wedel.
Substudies Committee
K.K. Teo (chair); A. Gavazzi, R.T. Tsuyuki, M. White, and R.
McKelvie.
Canadian Cardiovascular Collaboration Project
Office (Hamilton, Ontario)
M. Anderson, I. Holadyk-Gris, K. Kucemba, J. MacKay, R.S.
McKelvie, M. Micks, D. Pericak, J. Pogue, S. Reeve, L. Robinson, R.T.
Tsuyuki, J. Tucker, E.M. Wiecek, Y. Wang, and S. Yusuf.
Core Laboratories
Neurohormones: P. Cernacek, M. Joyal, N. Poitras, J.L. Rouleau,
M. White, P. Sirois, Montréal; M. Bevilacqua, R. Latini
(coordinator), S. Masson, M. Torri, Milano; C. Hall, Norway; Nuclear
Cardiology: R.J. Burns, T. Heeney, S. Tadros,
Toronto.
Manuscript Writing Committee
Michel White, MD (leader); Salim Yusuf, FRCP, DPhil; Robert S.
McKelvie, MD, PhD; Danny Pericak, MD; James Young, MD; Roberto Latini,
MD; Janice Pogue, MA, MSc; Robert J. Burns, MD; Jeffrey
Probstfield, MD; Ross T. Tsuyuki, PharmD, MSc; Aldo P. Maggioni,
MD; Álvaro Avezum Jr, MD; and Jean L. Rouleau, MD.
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Footnotes |
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1 For a complete list of the members of the Writing Committee, please see the Appendix.
Received April 19, 1999; revision received August 25, 1999; accepted September 7, 1999.
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