European Journal of Heart Failure

European Journal of Heart Failure 2003 5(5):659-667; doi:10.1016/S1388-9842(03)00163-6

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© 2003 European Society of Cardiology

Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON)

Jay N. Cohn^a,*, Marc A. Pfeffer^b, Jean Rouleau^c, Norman Sharpe^d, Karl Swedberg^e, Matthias Straub^f, Curtis Wiltse^g, Theressa J. Wright^g and for the MOXCON Investigators

^a Cardiovascular Division Mayo Mail Code 508, University of Minnesota Medical School 420 Delaware Street SE, Minneapolis, MN 55455, USA
^b Brigham and Women's Hospital, Harvard Medical School Boston, MA, USA
^c University of Toronto Toronto, Ont., Canada
^d University of Auckland Auckland, New Zealand
^e Sahlgrenska University Hospital Göteborg, Sweden
^f Solvay Pharmaceuticals B.V., Weesp The Netherlands
^g Eli Lilly and Company Indianapolis, IN, USA

^* Corresponding author. Tel.: +1-612-625-5646; fax: +1-612-624-2174. E-mail address: cohnx001{at}umn.edu

	Abstract

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. The following... References

 
Background: The association between sympathetic activation and mortality in chronic heart failure and the favorable effect of beta blocking drugs has raised the possibility of therapeutic efficacy for central sympathetic inhibition with sustained-release (SR) moxonidine, an imidazoline receptor agonist.

Methods: A randomized double-blind, placebo-controlled trial was initiated in 425 centers in 17 countries with a plan to enter 4533 patients with New York Heart Association class II–IV heart failure and a reduced ejection fraction. Moxonidine SR or matching placebo was titrated to a target dose of 1.5 mg BID. The trial was powered to detect a 20% reduction in mortality, which required a total of 724 deaths.

Findings: An early increase in death rate and adverse events in the moxonidine SR group led to premature termination of the trial because of safety concerns after 1934 patients were entered. Final analysis revealed 54 deaths (5.5%) in the moxonidine SR group and 32 deaths (3.4%) in the placebo group during the active treatment phase. Survival curves revealed a significantly (P=0.012) worse outcome in the moxonidine SR group. Hospitalization for heart failure, acute myocardial infarction and adverse events were also more frequent in the moxonidine SR group. Plasma norepinephrine was significantly decreased by moxonidine SR (–18.8% from baseline) vs. placebo (+6.9%).

Interpretation: Early termination of the trial limited conclusions regarding the long-term effects of central sympathetic inhibition. Nonetheless, the excess early mortality and morbidity suggest the likelihood of an adverse effect of moxonidine SR and raise concerns regarding the efficacy of generalized sympathetic inhibition in heart failure.

Key Words: Mortality • Moxonidine • Chronic heart failure

Received September 12, 2003; Accepted September 13, 2003

	1. Introduction

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. The following... References

 
The demonstrated relationship between plasma norepinephrine (PNE) levels and mortality in chronic heart failure [1–3] has raised the hypothesis that sympathetic nervous system (SNS) stimulation as a compensatory response in heart failure may itself contribute to adverse outcomes. Indeed, tracer kinetic studies in patients with heart failure have demonstrated increased norepinephrine spillover from the heart [4] that may contribute directly to myocyte damage [5]. The efficacy of beta blocking drugs in slowing progression of the disease and prolonging survival [6–10] has been viewed as confirmation for a deleterious effect of SNS stimulation on the heart. In addition, however, SNS stimulation induces vasoconstriction that may impair tissue perfusion and raise the impedance to left ventricular (LV) ejection [11]. Such peripheral vasoconstrictor effects could contribute to the progression of LV dysfunction and remodeling [12].

Increased PNE levels are observed not only in symptomatic heart failure but also in asymptomatic individuals with LV dysfunction [13]. Increased efferent sympathetic nerve traffic in heart failure is consistent with central activation [14]. Thus, a strategy to inhibit the SNS centrally would be a direct test of the hypothesis that sympathetic activation contributes to morbidity and mortality at all stages of heart failure. This approach might have the advantage of providing inhibition of both the cardiac and peripheral effects of SNS, which might enhance tolerability and efficacy. Furthermore, since PNE levels may serve as a guide to central inhibition [15], dose titration and its relationship to outcomes could potentially be quantitated better with a central SNS inhibitor than with beta blocker therapy.

Previous short-term trials with central sympathetic inhibiting drugs have provided encouraging data based on favorable hemodynamic effects and symptomatic improvement [16,17]. Moxonidine is a centrally-acting imidazoline receptor agonist that has been well-tolerated as an effective anti-hypertensive agent. Since the standard preparation of the drug, which is widely used in hypertension, exerts only a transient reduction in PNE [18], a sustained-release preparation of moxonidine (moxonidine SR) was developed. In preliminary dose-response trials with the new formulation of moxonidine SR in patients with heart failure, a prominent and sustained dose-dependent reduction of PNE was observed [19,20].

The moxonidine congestive heart failure trial (MOXCON) was, therefore, undertaken to evaluate the long-term efficacy of this central sympathetic inhibitor on outcomes in patients with varying degrees of chronic heart failure treated with all other background therapy.

	2. Methods

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. The following... References

 
The study was designed as a randomized, double-blind, placebo-controlled trial in patients with New York Heart Association (NYHA) class II–IV heart failure recruited in 425 centers in 17 countries. The study was approved by the institutional review board at each center. Since the goal was to study maximal well-tolerated central sympathetic inhibition, the study was designed as a forced titration from an initial low dose to a dose shown in preliminary studies to exert a prominent effect on PNE levels [20]. The primary end-point selected was all-cause mortality. Conduct of the study was overseen by Executive and Steering Committees, a Clinical End-Point Committee (CEC) to adjudicate events and a Data Monitoring Board (DMB) to monitor outcomes.

2.1. Study protocol
Patients 18 years of age or older with symptomatic heart failure (NYHA II, III or IV) were screened for eligibility based on an LV ejection fraction (EF) 35% by radionuclide ventriculography (MUGA) or contrast ventriculography, or an EF 35% by echocardiography when accompanied by an end-diastolic LV diameter 3.2 cm/m² BSA. A stable regimen of cardiovascular drug therapy was required, with no drugs being introduced or withdrawn for the month before randomization and no dosage change for the week before randomization. The initial protocol excluded beta blocker therapy but it was later allowed after the efficacy of carvedilol, bisoprolol and metoprolol was demonstrated in clinical trials [7–9].

Patients were excluded if they had a myocardial infarction or coronary reperfusion procedure within 3 months, a history of syncope within 3 months, the likelihood of cardiac surgery within 6 months, heart block of second degree or greater, angina occurring more than two times daily, a supine systolic blood pressure 85 mmHg, hemodynamically significant valvular or LV outflow tract obstruction, reversible active myocardial disease or severe concomitant disease likely to reduce life expectancy to less than 5 years, including reduced renal function (creatinine2.7 mg/dl). Drug exclusions included initiation of beta blocker therapy within the 6 months prior to randomization, use of clonidine or rilmenidine, use of tricyclic antidepressants or prior use of moxonidine.

Eligible patients who gave informed consent were randomly assigned to receive placebo or moxonidine SR using a centrally administered Interactive Voice Response System that also was used for drug management. Moxonidine SR or matching placebo was initiated at a dose of 0.25 mg BID, which could be increased at 1–2 week intervals to doses of 0.5, 1.0 and 1.5 mg BID. The dose was to be increased at sequential visits until the target dose had been reached unless symptomatic hypotension, worsening renal function, or other severe side effects were noted. This variable duration period of dose adjustment was identified as the dose optimization phase. After final titration had been achieved, patients were to return at 3-month intervals until termination of the trial. This period was identified as the dose maintenance phase. These two phases together were classified as the active treatment phase.

Because of concern about possible rebound sympathetic activation when the drug was withdrawn [18], the protocol required down-titration of the drug over 1 week at the end of the study in all patients who achieved the two highest doses of moxonidine SR (1.0 and 1.5 mg BID). The 2-week interval after drug termination was identified as the dose tapering (week 1) and washout (week 2) phases. Patients who withdrew permanently and prematurely from active treatment were transferred to the dose tapering and washout phases (if required) and were followed until study termination.

Follow-up consisted of clinical observation at each visit as well as routine laboratory tests. PNE and plasma brain natriuretic peptide (BNP) were to be measured at baseline, 3 months, 6 months and annually thereafter. The primary end-point was all-cause mortality. Secondary end-points were: (1) the combination of all-cause mortality and hospitalizations due to worsening heart failure; (2) hospitalization due to worsening heart failure; (3) cardiovascular mortality and (4) the effect of changes in PNE and BNP on all-cause mortality.

2.2. Statistical methods
The study was designed with power to detect a 20% reduction in mortality from an estimated 2.5 year all-cause mortality rate in the placebo arm of 22.75%. This estimate was based on previous trial data supplemented by consideration that MOXCON mandated that not more than 50% of patients could be in NYHA Class II and that, after an amendment allowing beta blocker co-therapy, approximately 30% of patients would be receiving these drugs. Based on a log-rank test with a two-sided 5% significance level and 80% power, 724 deaths were required and approximately 4533 patients would be randomized and followed until the 724 deaths had occurred. The primary efficacy component was to be assessed by monitoring four times (when 25, 50, 75 and 100% of the expected 724 deaths had occurred) over the course of the study.

In order to evaluate efficacy with a view to stopping the study for ethical reasons due to superior efficacy of the study drug, a stopping boundary was applied to maintain an overall two-sided alpha level of 0.05. The interim analysis after 25% of the 724 deaths was to be conducted at the nominal two-sided 0.0001 level, the interim analyses after 50 and 75% were to be conducted at the nominal 0.001 level, and the final study analysis was to be conducted at the nominal 0.049720 level. The nominal level at the end of the trial was determined using the method of Armitage et al. [21]. The DMB was also to conduct safety-monitoring reviews at least every 6 months throughout the course of the study. The DMB adopted a safety-stopping criterion of a 20% increase in all-cause mortality for moxonidine SR above placebo with a difference being statistically significant at the 5% one-sided level. Major clinical end-points were assessed by a blinded CEC using pre-specified criteria.

Time-to-event (‘survival’) variables were analyzed using the log-rank test, stratified by baseline NYHA class. Survival curves were generated using the Kaplan–Meier method. The change in PNE from baseline to end-point was analyzed by an analysis of covariance model which included the effects of treatment and the baseline PNE value; least squares means were reported from this analysis. The 95% confidence intervals for the difference in the incidence of treatment-emergent adverse events during the active treatment phase were calculated for all events with an incidence of at least 1% for the moxonidine SR group.

	3. Results

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. The following... References

 
Randomization began on May 25, 1998, and the study was terminated on the recommendation of the DMB on March 12, 1999. At the time of termination 1934 patients had been randomized into the trial and received study drug (intent-to-treat population) out of 2613 patients screened for participation; 990 of the randomized patients were assigned to moxonidine SR therapy and 944 to placebo. The baseline characteristics of these patients are shown in Table 1.

View this table: [in this window] [in a new window]   Table 1 Baseline characteristics of patients

 
The recommendation of the DMB was based on mortality data available at the safety review on March 1, at which time 66 deaths had been reported, 42 in the moxonidine SR treatment group and 24 in the placebo treatment group. The P-value of 0.027 was lower than the DMB's predetermined safety-stopping rules. After consultation with the Executive Committee, it was agreed to delay the decision for another week while randomization was stopped and while the Executive Committee explored revision of the protocol to slow the dose titration schedule and eliminate the highest dose of 1.5 mg BID. These suggested changes to the protocol were based on the speculation (not confirmable from the data analysis available at that time) that adverse effects of too rapid and too severe inhibition of the SNS could have accounted for the apparently adverse early experience. On March 8 mortality data were updated to reveal four more deaths in the moxonidine SR group and only one in the placebo group. The sponsor terminated the trial on recommendation of the DMB on March 12 despite the Executive Committee's preference to revise the protocol.

Final data on mortality and morbidity during the various phases of the trial (Table 2) include deaths that occurred prior to March 12 but not reported at the time of the DMB review. The mortality rate in the moxonidine SR arm during the active treatment phase (n=54, 5.5% of randomized patients) was higher than in the placebo group (n=32, 3.4%). Kaplan–Meier curves demonstrated significantly poorer survival in the moxonidine SR group (P=0.012) (Fig. 1).

View this table: [in this window] [in a new window]   Table 2 Events in randomized patients by study phasea

 

View larger version (7K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Kaplan–Meier survival curves (all-cause mortality) during active treatment phase of MOXCON.

 
Causes of death during the active treatment phase were adjudicated by the CEC (Table 3). The excess deaths in the moxonidine SR group appeared to be related to both an increases in deaths classified as sudden and an increase in deaths classified as pump failure. Other adjudicated end-points also were more common in the moxonidine SR group, including hospitalization for worsening heart failure (75 [7.6%] moxonidine SR patients vs. 54 [5.7%] placebo patients) (Table 2) and acute myocardial infarction, which occurred in 16 (1.7%) moxonidine SR patients and 8 (0.8%) placebo patients. Ninety-two patients were prematurely discontinued from the trial for reasons other than death. In 37 instances discontinuation was related to an adverse event (27 moxonidine SR, 10 placebo) and in 48 instances the patient withdrew consent (25 moxonidine SR, 23 placebo). Heart transplant was performed in one placebo patient. One moxonidine SR patient was discontinued by the physician and five moxonidine SR patients but zero placebo patients were lost to follow-up.

View this table: [in this window] [in a new window]   Table 3 Adjudicated causes of death during active treatment phase

 
A possible relationship between mortality and dosage of moxonidine SR administered at time of death was clouded by the forced dose-titration study design. In this design patients who tolerate the drug are up-titrated but those who do not tolerate the drug often remain on low doses. The possibility of events occurring if patients had discontinued the drug for side effects or were non-compliant with the assigned drug was difficult to assess. In the 2-week dose tapering and washout phases, a time period not included in the primary analysis, four deaths occurred, three in the moxonidine SR group and one in the placebo group. No pattern could be established that mortality was associated with discontinuation or interruption of moxonidine SR therapy.

During the active treatment phase, treatment-emergent adverse events were more common in the moxonidine SR group than in the placebo group. Adverse events were reported in 68% of the moxonidine SR group and 53.7% of the placebo group (P<0.001). Specific adverse events statistically more common in the moxonidine SR group than in the placebo group and occurring in at least 1% of the moxonidine SR patients are listed in Table 4.

View this table: [in this window] [in a new window]   Table 4 Treatment emergent non-endpoint adverse eventsa during active treatment phase

 
Supine PNE levels were available only at baseline, 3 and 6 months because the MOXCON trial was terminated before any of the patients reached the 1-year anniversary of randomization. PNE at the time of last measurement was strikingly reduced in those patients assigned to moxonidine SR (median value 287 pg/ml) compared with those randomized to placebo (398 pg/ml). The adjusted mean change from baseline averaged 31 pg/ml (+6.9% from baseline) in the placebo group and –84 pg/ml (–18.8% from baseline) in the moxonidine SR group (P<0.001). The cumulative distributions of last measured PNE level in surviving patients are shown in Fig. 2. Similar distributions were observed in the patients who died (Fig. 3), thus not providing support for the hypothesis that unusually severe suppression of PNE accounted for the excess mortality.

View larger version (6K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Cumulative distribution function of PNE in survivors at end-point (3 or 6 months) in placebo and moxonidine SR groups.

 

View larger version (5K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 Cumulative distribution of PNE at last measurement in patients who died after the 3- or 6-month measurement. PNE in the moxonidine SR group does not appear much different than in survivors (Fig. 2).

 

	4. Discussion

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. The following... References

 
The primary objective of MOXCON was to compare moxonidine SR vs. placebo with respect to the time to death from any cause (all-cause mortality). The data revealed that moxonidine SR therapy was associated with excess short-term mortality and morbidity. Whether the adverse effect can be attributed to the protocol design (forced titration at 1–2 week intervals to a high dose) or to the mechanism of action of the drug, the data suggest that central inhibition of the SNS is not safe in patients with heart failure.

The total number of deaths in the MOXCON study was 105 and 14.5% of the target number of 724 (Table 2). Although the highly significant excess deaths in the moxonidine SR group could have been a chance occurrence, the clustering of other cardiovascular events in this treatment arm and the higher incidence of other adverse events in the moxonidine SR treatment group suggest that the adverse effects were drug related.

The total daily dose of the SR formulation of moxonidine SR used in MOXCON was several-fold higher than that of the immediate-release marketed formulation of moxonidine [2] used in the treatment of hypertension and in earlier investigations in heart failure [18]. In addition, the reduction of PNE following moxonidine SR administration was more sustained and greater than with the immediate-release formulation [18]. A possible relationship between mortality and dosage of moxonidine SR administered at time of death was clouded by the forced dose-titration study design. However, the MOXCON data provide no conclusive support for the hypothesis that the higher doses or more profound reduction in PNE were the cause of the excess mortality.

Two randomized, double-blind, placebo-controlled clinical trials conducted with moxonidine SR in patients with congestive heart failure demonstrated that patients were able to tolerate weekly up-titration to doses as high as those used in MOXCON [19,20]. In designing the MOXCON trial, the Steering Committee and Sponsors felt that central suppression with modest decrements in synaptic cleft and in circulating norepinephrine levels might be better tolerated than receptor inhibition and, therefore, a more rapid titration might be possible. Hence, weekly titration schedules were allowed in MOXCON. Whether this rapid titration contributed to death in these patients cannot be ascertained.

The findings in MOXCON mandate re-examination of the hypothesis underlying the trial. One of the proposed benefits of moxonidine SR was inhibition of the vasoconstrictor as well as the cardiac stimulation from SNS stimulation. However, a previous study with the alpha receptor blocker prazosin in heart failure revealed no benefit on outcome [22]. Furthermore, the alpha blocker arm of the anti-hypertensive and lipid-lowering treatment to prevent heart attack trial was terminated prematurely because of an excess in heart failure events [23]. Thus, there appears to be no long-term benefit from inhibition of the vasoconstrictor effects of SNS stimulation.

The benefit of beta receptor blockade in heart failure has been demonstrated in several controlled trials [7–10]. Gradual dosage titration has been used in these trials because of possible symptom worsening during the early treatment phase. In contrast to the MOXCON data, no excess early mortality has been reported in any of these studies. The SNS inhibition in MOXCON could have been too rapid and effective in comparison to what is achieved by slow titration of a beta blocker. It is also possible that the pharmacologic benefit of beta blockade in heart failure is at least partly through a mechanism different than that resulting from a decrease in sympathetic nerve traffic. Renin inhibition by beta-1 receptor blockade with reduction in angiotensin II levels may be an important non-adrenergic mechanism for efficacy of beta blockers [24]. SNS activation in chronic heart failure remains important in the pathophysiology of the syndrome, but the optimal counteraction of this activation is still unclear and requires further study.

	Appendix A. The following individuals contributed to the MOXCON trial

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. The following... References

 
Executive and Steering Committee: Chairman, Jay N. Cohn, USA; Executive Members: Marc Pfeffer, USA; Jean-Lucien Rouleau, Canada; Norman Sharpe, New Zealand; Karl Swedberg, Sweden; Members: Murray Esler, Australia; David Kaye, Australia; Dia El. Allaf, Belgium; Jose Antonio Ramires, Brazil; Debra Isaac, Canada; John D. Parker, Canada; Vladimir Stanek, Czech Republic; Torben Haghfelt, Denmark; Faiez Zannad, France; Wolfgang Motz, Germany; Pal Karpati, Hungary; Peter Crean, Ireland; P.J.L.M. Bernik, Netherlands; Gary Gordon, New Zealand; Andre Saaiman, South Africa; Maria Schaufelberger, Sweden; Mau-Song Chang, Taiwan; Henry Dargie, UK; Claude Benedict, USA; Michael Bristow, USA; Wayne Levy, USA; Data Monitoring Board: Chariman, Lars Wilhlmsen, Sweden; Members: Kenneth Dickstein, Norway; Gary Francis, USA; Stuart Pocock, UK; Janet Wittes, USA; Clinical Endpoints Committee: Chairman, Marc Pfeffer, USA; Members: Leif Erhardt, Sweden; Jalal Ghali, USA; Philippe Lechat, France; Wolfgang Motz, Germany; Jean-Lucien Rouleau, Canada; Scott Solomon, USA; Amoux Blanchard, USA; Anique Ducharme, USA; Renee Guertin, USA; Hanns Tillmann, USA.

MOXCON Investigators: Australia: J. Amerena, R. Amor, L. Ayres, B. Ayres, D. Coulshed, J. Counsell, D. Cross, R. Dick, M. Esler, P. French, A. Galbraith, P. Garrahy, J. Horowitz, L. Howes, B. Jackson, J. Johns, J. Karrasch, D. Kaye, C. Keightley, A. Keogh, G. Lane, J. Lefkovits, J. Leitch, G. Leitl, W. McKenzie, G. O'Driscoll, A. Sindone, B. Singh, P. Thompson, W. Walsh, R. Yeend. Belgium: Boutefeu, T. Bouvy, M. Castadot, J. Chaudron, D. Duprez, D.El. Allaf, G. Jouret, F. Martens, J. Melchior, B. Paelinck, W. Van Mieghem, M. Vandermotte. Brazil: A. Baretto, M. Batloumi, A. Carvalho, I. Castro, A. Ciogna, O. Coelho, D. Dauar, J. Neto, S. Rassi, J.F. Saraiva. Canada: M. Arnold, J. Audet, R. Baigrie, R. Bauer, J. Bedard, R. Bessoudo, R. Bhargava, T. Bhesania, M.T. Cheung, G. Chua, W. Czarnecki, F. Delage, E. Gangbar, V. Gebhardt, D. Gossard, G. Goulet, A. Grover, J. Howlett, T. Huynh, J. Hynd, D. Isaac, M. Khouri, S. Kouz, K. Kwok, M.H. Leblanc, J. Lenis, M. Levy, P. Liu, B. Lubelski, P. Ma, C. Maranda, R. McKelvie, G. Moe, A. Morris, J. Parker, Y. Pesant, D.C. Phaneuf, R. Roux, F. Sestier, S. Smith, H. Strauss, B. Sussex, P. Talbot Jr., M. White, L. Yao. Czech Republic: J. Bultas, P. Cerny, J. Danczik, B. Filpensky, A. Furst, P. Havranek, P. Jansky, P. Jebavy, L. Kamenik, L. Kuchar, P. Lindovsky, Z. Lorenc, J. Malkova, E. Mandysova, O. Mayer Sr., J. Nemec, T. Paulysko, J. Povolny, M. Richter, M. Rubacek, B. Semrad, M. Skvarilova, J. Smid, V. Stanek, R. Stipal, J. Toman, J. Widimsky. Denmark: E. Agner, N. Gadsboell, T. Haghfelt, N. Keller, K. Lyngborg, V. Rasmussen, K. Skagen, C. Torp-Pedersen. France: G. Amat, N. Baille, J.P. Betinchant, Z. Chati, Dambrine, J. Demarcq, B. D'Hautefeuille, T. Drawin, Dugrand, C. Fournier, G. Hannebicque, J.P. Houppe, S. Levy, T. Olive, J.E. Poulard, J. Puel, B. Thiel, F. Zannad. Germany: C. Bergmeier, M. Bohm, H. Darius, W. Delius, R. Dietz, R. Erbel, P. Gaudron, Gerono, M. Haass, G. Hasenfub, L. Hennig, C. Holubarsch, T. Ittel, K. Karsch, H. Katus, C. Kerber, B. Kobe, M. Kochs, K.H. Konz, S. Krabbe, B. Maisch, J. Meier, V. Meyer, V. Mitrovic, W. Motz, B. Mox, K. Prztanski, Rhule, Sauer, W. Schiwy, K. Schmailzl, H.C. Schober, K. Schueren, H. Schulz, W. Sehnert, K. Taubert, W. Thimme, Urbaszek, G. Weyers, E. Wolff. Hungary: M. Csnady, L. Cserhalmi, I. Edes, C. Farsang, T. Fenyvesi, D. Gelleri, I. Hegyi, A. Janosi, E. Kalo, K. Karlocai, P. Karpati, A. Kovacs, P. Kovacs, G. Kurta, F. Lakstos, M. Lengyel, J. Lippai, B. Mezey, I. Preda, J. Rapi, M. Rusznak, G. Sallai, M. Sereg, T. Sydo, J. Tarjan, J. Tenczer, S. Timar, P. Valvi, K. Zamolyi. Ireland: J. Barton, F. Bradbury, G. Bury, J. Clarke, P. Crean, J. Fennell, M. Laher, F. Lavin, D. McCafferty, P. McCormack, K. McDonald, K. McGarry, P. McGarry, B. McMahon, T. Meany, D. Moore, S. Murphy, B. O'Doherty, M. O'Reilly, M. Ryan, E. Shanahan, B. Silke, D. Sugrue. Netherlands: S. Braat, J. Cornel, W. DeVoogt, F. Den Hartog, P.H.J.M. Dunselman, E.J.A.M. Gobel, N.J. Holwerda, J. Hoorntje, W. Jaarsma, L. Jansen, J. Kragten, G. Laarman, A.H. Liem, D.J.A. Lok, A.H.E.M. Maas, H. Michels, P. Nierop, A. Ramdat Misier, L. Slegers, R. Sloos, S. Strikwerda, P.H. Van Der Burgh, E. Van Der Wall, L. Van Kempen, D. Van Veldhuisen, L. Van Wijk, J. Wesdorp, A. Withagen. New Zealand: R. Doughty, D. Friedlander, G. Gordon, A. Hamer, H. Hart, D. Jardine, K. Logan, M. Lund, L. Nairn, M. Richards, D. Scott, M. Williams. South Africa: A.M. Baig, S. Cassim, P. Commerford, T. Dalby, A. Doubell, M. Essop, E. Klug, J. Marx, M. Mpe, D. Myburgh, D. Naidoo, A. Saaiman, P. Sareli, D. Skudicky, D. Skudicky, R. Spammer, R. Theron, G. Vawda. Sweden: G. Agert, U. Ahremark, U. Ahremark, C. Bergh, M. Edner, S. Ekdahl, L. Erhardt, C. Hoglund, L. Kareld, L. Klintberg, E. Pantev, M. Schaufelberger, C. Wettervik. Taiwan: G. Bih-Fang, M. Chang, J. Chen, M. Chen, K. Chu, P. Ding, G. Guo, Y. Ko, W. Lai, C. Lee, Y. Lee, M. Mao-Young-Fu, R. Pan, J. Teng, C. Tsai, L. Tsai, W. Wen, J. Wu. United Kingdom: M. Al-Khafaji, R. Baxert, P. Bennett, A. Coats, Cobbe, A. Cowley, H. Dargie, F. Dunn, I. Findlay, S. Gibbs, R. Greenbaum, P. Groves, A. Lahiri, E. Leatham, G. Lip, M. Metcalfe, D. Murdoch, G. Murtagh, A. Pell, J. Pohl, I. Squire, I. Starkey, J. Stephens, J. Swan, A. Timmis, R. Whale. USA: W. Abraham, P. Alagona, I. Anand, J. Anderson, J. Aranda, M. Arendt, M. Ariani, M. Ashraf, J. Bailey, W. Bailey, D. Banish, L. Basta, C. Benedict, T. Bennett, V. Bethala, G. Bhaskar, S. Bilazarian, N. Bittar, R. Bourge, M. Bristow, J. Burke, S. Butman, W. Carlson, P. Carson, J. Carter, D. Chinoy, B. Cohen, H. Cilfer, C. Corder, W. Cotts, K. Danisa, D. Dawley, T. Demarco, V. Dequattro, K. Desai, T. Donahue, M. Dowd, E. Eichhorn, H. Eisen, U. Elkayam, S. Ellahham, K. Ferdinand, L. Ford, M. Garcia-Palmieri, T. Gardner, J. Ghali, M. Gheorghiade, T. Giles, M. Givertz, D. Goldberg, D. Goldscher, S. Goldsmith, D. Gottlieb, S. Gottlieb, B. Greenburg, M. Greenspan, W. Hager, T. Hastings, E. Hernandez-Lopez, R. Hershberger, M. Higginbotham, G. Hill, A. Jain, P. Kakavas, J. Kalman, R. Karlsberg, M. Kates, S. Katz, D. Kereiakes, B. Kerzner, S. Khan, R. Kipperman, G. Koshkarian, J. Kostis, S. Krueger, M. Kukin, G. Lamas, J. Lash, T. LeJemtel, R. Levine, W. Levy, W. Lewis, G. LiMandri, P. Linz, D. Loew, E. Loh, I. Loh, M. Luu, F. Maggiacomo, D. Mann, M. McIvor, F. McGrew, R. Miller, S. Mohiuddin, P. Moore, J. Morledge, R. Moyer, W. Mullican, M. Munger, D. Munoz, D. Murray, R. Muse, C. Newton, I. Niazi, J. Nicklas, P. Nicol, A. Niederman, J. O'Brien, J. O'Bryan, W. Old, W. O'Riordan, P. Pak, G. Pauchis, J. Perry, M. Pfeffer, J. Plehn, C. Porter, R. Preston, H. Punzi, P. Rahko, R. Ramadurai, T. Ramahi, B. Ramo, H. Reddy, G. Revtyak, D. Richards, R. Rothbart, D. Ruff, J. Sackner-Bernstein, R. Sanchez, C. Schulman, B. Schwartz, P. Siegel, M. Semigran, M. Silver, A. Simpson, M. Slawsky, G. Smith, K. Smith, W. Smith, E. Smith III, F. Snow, J. Snyder, J. Sorensen, D. Stapleton, D. Strutin, R. Sweidan, L. Taber, M. Tonkon, J. Torrelli, B. Uretsky, K. Vaska, W. Voyles, J. Walker, M. Walsh, M. Weber, R. Weiss, J. Wertheimer, J. Wilson, A. Wong, E. Wong, C. Yancy, J. Young.

	Acknowledgements

 
Sponsored and supported by Eli Lilly and Company and Solvay Pharmaceuticals.

	References

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. The following... References

 

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