Is beta-blockade useful in heart failure patients with atrial fibrillation? An analysis of data from two previously completed prospective trials

The European Journal of Heart Failure 4 (2002) 489 494 Is beta-blockade useful in heart failure patients with atrial fibrillation? An analysis of data from two previously completed prospective trials Jeffrey W.H. Fung, Skiva K.W. Chan, Leata Y.C. Yeung, John E. Sanderson* Division of Cardiology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital Shatin, NT, Hong Kong SAR, PR China Received 29 May 2001; received in revised form 26 November 2001; accepted 12 January 2002 Abstract Background: Beta-adrenergic blockade is of proven value in chronic heart failure. It is uncertain, however, if beta-blockade provides a similar degree of clinical benefit for heart failure patients with atrial fibrillation (AF) as those in sinus rhythm (SR). Aims: To compare the effectiveness of beta blockade in patients with heart failure and AF. Methods: Patients with chronic heart failure were randomized to treatment (double blind) with metoprolol 50 mg twice daily or carvedilol 25 mg twice daily in addition to standard therapy. Response was assessed after 12 weeks by a quality of life questionnaire, New York Heart Association class, exercise capacity (6-min walk test), radionucleotide ventriculography for LVEF, 2-D echocardiography measurement of left ventricular (LV) dimensions and diastolic filling and 24-h electrocardiograph monitoring to assess heart rate changes. Results: Both beta-blockers produced significant improvements in LVEF in both the SR group: (q6"10% at 12-week, P-0.001) and the AF group: (q11"9% at 12-week, P-0.05). However, significant improvement in symptoms (P-0.001) and exercise capacity (P-0.001) were observed only in the SR group but not in the AF group despite a significant improvement in LVEF. Conclusion: Beta-blockers were effective in improving LV ejection fraction in chronic heart failure patients in either SR or AF but had less effect on symptoms and exercise capacity in those with AF. 2002 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved. Keywords: Atrial fibrillation; Beta-blockers; Heart failure 1. Introduction It is well proven that beta-adrenergicblockade is useful for patients with chronic heart failure w1,2x. The MERIT-HF study and several other studies have provided strong evidence supporting favourable effects of b- blockade on left ventricular (LV) ejection fraction and the combined risk of death and hospitalization for heart failure w3,4x. Metoprolol and carvedilol were the betablockers studied in these trials w1 4x. The effects of metoprolol and carvedilol in the treatment of chronic heart failure are comparable, as we have previously reported w5x. It is estimated that atrial fibrillation (AF) was present in 15 30% of patients with dilated cardiomyopathy and moderate to advanced heart failure w6 8x. Beta-blockers have been shown to reduce arrhythmic *Corresponding author. Tel: q852-2632-2064; fax: q852-2637- 3852. E-mail address: jesanderson@cuhk.edu.hk (J.E. Sanderson). events and have a significant impact on AF w9 11x. However, there is limited data about the clinical benefit, if any, of using beta-blockers in heart failure patients with AF. Therefore, we have analyzed two previous prospective trials w5,12x to compare the clinical benefits of beta-blockers, either metoprolol or carvedilol, in the treatment of chronic heart failure patients with either sinus rhythm (SR) or AF. Response was assessed by symptoms, exercise capacity, LV systolic and diastolic function and heart rate changes over a 3-month period. 2. Methods 2.1. Trial design Both trials were prospective, parallel group, double blind-controlled trials with similar design w5,12x. Inclusion criteria of the two studies were identical. Patients with typical symptoms of heart failure and reduced LV 1388-9842/02/$ - see front matter 2002 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved. PII: S1388-9842Ž02.00031-4

490 J.W. Fung et al. / The European Journal of Heart Failure 4 (2002) 489 494 ejection fraction (-0.45) were recruited into the studies. The first study compared metoprolol to celiprolol in patients with chronic heart failure w12x and the second study compared metoprolol to carvedilol w5x. Patients were divided into SR and AF groups. Only patients who received either metoprolol or carvedilol were recruited for analysis because the beneficial effects of these two beta-blockers have been well proven in other heart failure trials w1 4x. There was a 4-week titration period, increasing the dose of carvedilol from 3.125 to 25 mg twice daily and metoprolol from 6.25 to 50 mg twice daily. Doses were increased at weekly intervals. Maintenance of doses was continued for 8 weeks (total of 12 weeks of treatment). At the end of 12 weeks, baseline measurements were repeated. Clinical assessment was carried out at 1, 2, 4 and 8 weeks. Compliance was checked by counting the remaining capsules at each visit. 2.2. Study objectives To compare the clinical benefits of beta-blockers in heart failure patients with either SR or AF, by assessment of symptoms (using the Minnesota Quality of Life Heart Failure Questionnaire), exercise capacity (6-min walk test), LV ejection fraction (measured by radionucleotide ventriculography and echocardiography) and heart rate changes (24-h ambulatory electrocardiograph (ECG) monitoring). The primary end points were symptom score, exercise time and LV ejection fraction. The study had a 90% power to detect a 55% reduction in symptoms score, a 20% increase in the 6-min walk time and a 12% increase in LV ejection fraction from baseline for each group, all of which would be considered clinically significant. 2.3. Study patients Patients with a clinical diagnosis of chronic heart failure who were on standard therapy with diuretics, digoxin- and angiotensin-converting enzyme inhibitors and with a LV ejection fraction of -0.45 (by radionucleotide ventriculography) were recruited. Patients were excluded if they had significant valvular heart disease as the etiology of LV dysfunction, active myocarditis, unstable angina, a documented history of sustained ventricular tachycardia or symptomatic nonsustained ventricular tachycardia or second- or third-degree atrioventricular block. Patients with chronic obstructive lung diseases, asthma, long-term alcohol or drug abuse or chronic renal failure (serum creatine )200 mmolyl), hepatic, hematological, neurological or collagen vascular disease were excluded. All subjects gave written informed consent, and the study was approved by the Ethics Committee of the Faculty of Medicine, the Chinese University of Hong Kong. 2.4. Study measurements Baseline measurements included assessment of symptoms using the Minnesota Heart Failure Symptom Questionnaire, New York Heart Association (NYHA) class and routine clinical examination (pulse, heart rate, sitting and standing blood pressure, examination of jugular venous pressure, position of the apex beat and presence or absence of a heart murmur or lung rales). A 6-min corridor walk test was carried out. Two baseline walk tests were carried out and the results averaged. Routine 2-D Doppler echocardiography was performed with measurement of LV dimensions. Pulse-wave Doppler echocardiography was performed to assess mitral inflow velocities. The usual variables were measured: peak early mitral filling velocity (E wave), peak atrial filling velocity (A wave), ratio of the peak early and atrial filling velocities (EyA), deceleration time of the E wave (DT) and isovolumicrelaxation time, as previously described w13x. Radionucleotide ventriculography was used to assess LV ejection fraction in the usual way. A 24-h ambulatory ECG monitoring was undertaken using the Marquette (Milwaukee, Wisconsin) MARS 8000 analyzer. Maximum, average and minimum heart rate analyses were undertaken. Routine blood laboratory tests were performed at baseline, and at 4 and 8 weeks. 2.5. Statistical analysis Differences between the AF and SR groups were carried out by repeated-measures analysis of variance for continuous variables (ANOVA) with Barlets test with homogeneity test if P-0.05, Friedman s test for non-parametric data and Fisher exact test for differences between proportions. Differences between baseline and week 12 within groups were tested by paired t-tests, and Wilcoxon matched pairs signed ranks test for nonparametricdata. The results are expressed as mean"s.e.m. Differences were considered significant if P-0.05. 3. Results 3.1. Subjects Sixty-three patients with a mean LV ejection fraction of 26"10% were in SR while 12 patients with a mean LV ejection fraction of 26"7% were in AF. In the SR group, 42 patients were taking metoprolol and the rest were taking carvedilol. In the AF group, 5 were taking metoprolol and 7 were taking carvedilol. There were no significant differences in age, gender or other baseline characteristics except that the AF group had lower exercise capacity than the SR group (Table 1). The majority of patients had idiopathicdilated cardiomyopathy (44%) with ischemic cardiomyopathy as the etiology in 25% and hypertensive heart disease in 30%.

J.W. Fung et al. / The European Journal of Heart Failure 4 (2002) 489 494 491 Table 1 Baseline clinical characteristics of study patients Sinus rhythm Atrial fibrillation P-value (ns63) (ns12) Age (years) 58.1 (1.6) 64.3 (3.4) 0.13 Range 20 86 43 80 Gender Male 50 9 Female 13 3 Etiology IDC 29 4 ICM 17 2 HTHD 17 6 NYHA functional class II 25 3 NYHA functional class III 37 9 NYHA functional class IV 1 0 Symptom questionnaire score 16.1 (1.5) 15.4 (4.9) 0.86 ETT (6-min walk, feet) 1210 (27) 908 (72) -0.001 Baseline blood pressure (mmhg) 125 (3)y76 (2) 127 (7)y73 (3) 0.70y0.58 Heart rate (beatsymin) 84.5 (1.7) 78.2 (2.7) 0.12 LVEF (%) 26.1 (1.3) 26.1 (2.3) 1.0 LVEDD (cm) 7.0 (0.1) 6.2 (0.3) 0.01 FS (%) 14.2 (0.6) 13.8 (1.1) 0.77 Treatment Frusemide 57 (90%) 11 (92%) Frusemide mean dose (mg) 59.3 (5.3) 69.1 (14.1) 0.47 ACEIyAIIRA 58 (92%) 11 (92%) Nitrates 40 (63%) 7 (58%) Values are mean"s.e.m.; ACEI, angiotensin-converting enzyme inhibitor; AIIRA, angiotensin II receptor antagonist; ETT, exercise tolerance test; FS, LV fraction shortening; HD, heart disease; HTHD, hypertensive heart disease; ICM, ischemic cardiomyopathy; IDC, idiopathic dilated cardiomyopathy; LVEDD, LV end-diastolic dimension; LVEF, LV ejection fraction (gated blood pool scan). All but one patient were taking an angiotensin-converting enzyme inhibitor or an angiotensin II receptor antagonist. The average daily dose of frusemide was similar in both groups. 3.2. Withdrawals In the SR group, 7 patients did not complete the study. The reason for withdrawal was mainly worsening of symptoms, in particular, weakness, dizziness and dyspnoea. One patient developed angioneuroticedema. In the AF group, 3 patients did not complete the study and the reasons for withdrawal were similar to that of the SR group. There was no difference between the SR and AF groups. 3.3. Symptoms The results of the symptom (quality of life) questionnaire score and assessment of NYHA functional class are shown in Table 2. A highly significant reduction in symptom questionnaire score was observed in SR group (P-0.001) but not in AF group. Neither the SR nor AF groups had any reduction of NYHA class though a trend (Ps0.07) of reduction was observed in the SR group after 12-weeks of beta-blocker therapy. However, there were no significant differences between SR and AF in terms of NYHA class (Ps0.104) and quality of life questionnaire score (Ps0.61) at the end of the study. 3.4. Blood pressure and heart rate (Table 2) At 12 weeks, beta-blockers produced a highly significantly reduction in systolic and diastolic blood pressures compared with baseline in SR group. In AF group, a reduction in systolic and diastolic blood pressures was also observed. At the end of the study, blood pressures were significantly lower in the AF group when compared to the SR group (Ps0.012). A significant reduction of maximum, average and minimum heart rate was observed in both the SR and AF groups at 12 weeks when compared to baseline. There was no difference in average heart rate in both groups at 12 weeks (64.6"1.4 beatsymin in SR and 63.4"2.6 beatsymin in AF). 3.5. Exercise capacity (Table 2) With similar degree of LV ejection fraction, the AF group had worse exercise capacity than the SR group at baseline (Table 1). At 12 weeks, a significant improve-

492 J.W. Fung et al. / The European Journal of Heart Failure 4 (2002) 489 494 Table 2 Effects of beta-blockers on symptoms, exercise capacity, blood pressure and heart rate (Mean"SEM) SR group AF group SR vs AF at 12- Baseline 12 weeks Baseline 12 weeks week, P-value Symptom questionnaire score 16.1 (1.5) 6.8 (1.1) *** 15.4 (5.0) 8.4 (3.6) 0.61 NYHA functional class I 0 6 0 0 II 25 42 3 6 III 37 8 9 3 IV 1 0 0 0 Mean 2.6 (0.07) 2.04 (0.07) 2.75 (0.13) 2.33 (0.17) 0.104 Blood Pressure (mmhg) SBP 125 (3) 117 (3) ** 127 (7) 98 (8) * 0.012 DBP 76 (2) 70 (2) *** 74 (3) 63 (4) * 0.09 Heart Rate (HR) (beatsymin) Maximum HR 123.9 (2.3) 104.6 (2.1) *** 161.8 (13.0) 122.6 (10.1) * Average HR 84.5 (1.7) 64.6 (1.4) *** 78.2 (2.7) 63.4 (2.6) ** 0.76 Minimum HR 59.7 (1.7) 48.6 (1.1) *** 50.0 (3.0) 41.7 (3.2) ** ETT (6-min walk, feet) 1210 (27) 1323 (31) *** 908 (71) 984 (90) -0.001 DBP, diastolic blood pressure; ETT, exercise tolerance time; NYHA, New York Heart Association; SBP, systolic blood pressure. *** P-0.001. ** P-0.01. * P-0.05 week 12 vs. baseline. ment in exercise capacity as measured by 6-min walk test was observed in the SR group only. Moreover, exercise capacity at 12 weeks in the SR group was better than that in the AF group (1323"31 feet vs. 984"90 feet, respectively, P-0.001). 3.6. LV systolic and diastolic functions (Table 3) Both groups showed significant improvement in LV ejection fraction with beta-blocker therapy. There was no difference in LV ejection fraction between the two groups at 12 weeks (32"1.6% in SR and 37"5.1 in AF). At 12 weeks, the SR group, but not the AF group, showed a significant reduction in LV end-diastolic dimension. Beta-blockers produced no change in peak mitral E wave velocity but prolonged the deceleration time of the mitral E value towards normal in both groups. 4. Discussion In this 3-month study comparing the clinical efficacy of beta-blocker therapy in chronic heart failure patients with either SR or AF, we have demonstrated that betaadrenergic blockade significantly improves LV ejection fraction in both groups. However, the benefit of betablocker therapy in improving exercise capacity and quality of life as reflected by the symptom questionnaire score could only be demonstrated in the SR group. Betablocker therapy lowered blood pressures in both groups. Table 3 Effects of beta-blockers on systolic and diastolic LV function SR group AF group SR vs AF at 12- Baseline Week 12 Baseline Week 12 week, P-value LVEF % 26"1.2 32"1.6 *** 26"2.3 37"5.1 * 0.32 LV FS 14.2"0.6 19.1"0.8 *** 13.8"1.1 23.1"2.5 * 0.07 LV edd (cm) 7.0"0.1 6.7"0.2 ** 6.2"0.3 6.0"0.1 0.1 Mitral E (cmys) 11.3"3.7 11.5"3.2 9.3"8.3 10.3"9.4 0.9 Mitral A (cmys) 9.1"3.3 12.4"3.3 NA NA NA EyA ratio 1.5"0.1 1.1"0.1 NA NA NA Mitral DT (ms) 145"9 208"11 *** 147"19 223"26 *** 0.6 LV edd, LV end-diastolic dimension; LVEF, LV ejection fraction; LVFS, LV fractional shortening; mitral A, peak velocity of mitral atrial wave; mitral DT, deceleration time of mitral E wave; mitral E, peak velocity of mitral early filling wave; NA, not applicable. *** P-0.001. ** P-0.01. * P-0.05 week 12 vs. baseline.

J.W. Fung et al. / The European Journal of Heart Failure 4 (2002) 489 494 493 Both groups showed a marked reduction in heart rates with beta-blocker therapy. With regard to LV diastolic function, significant prolongation of mitral E deceleration time was observed in both groups. In our study, 16% of patients with chronic heart failure were in AF. Such a proportion is consistent with other studies which range from 15 to 30% w6 8x. The proportion of heart failure patients with AF in V-HeFT I w14x was 16% and in V-HeFT II w15x was 13%. Thus, our study cohort is quite similar to other heart failure studies. However, the small number of patients in AF when compared with those in SR makes statistical analysis difficult w6x. In this study, beta-blocker therapy was shown to be equally effective in improving LV systolic function in heart failure patients with either AF or SR. In a retrospective analysis of the US Carvedilol Heart Failure Trials Program w16x, a similar degree of improvement in LV ejection fraction in patients with AF by carvedilol when compared to placebo was also observed. There was a non-significant trend of reduction in combined endpoints of death or heart failure hospitalization in the carvedilol group. However, different results were observed in the CIBIS II trial w17x using bisoprolol. The survival benefit and reduction in heart failure hospitalization by bisoprolol was not observed in those patients in AF. This suggests that different beta-blockers may not have the same benefits to heart failure patients with AF. It is interesting to note that, although the LV ejection fraction was similar in both groups at baseline and end of week 12 in the present study, patients in AF had a worse exercise capacity and were more symptomatic than patients in SR. Moreover, significant improvement in exercise capacity and symptoms by beta-blockers was only observed in the SR group. It has also been shown that baseline heart rate and heart rate changes are significantly related to prognosis in patients with heart failure w17x. In the present study, however, rate control differences after beta-blocker therapy cannot explain the difference as the maximum, average and minimum heart rates were similar in both groups after 12 weeks of therapy. There are two possible explanations why patients in AF were more symptomaticand had worse exercise capacity. First, statistical error might be responsible, as the sample size of patients in AF was small. The second explanation is that it might be related to the physiological impact of ventricular rate irregularity. In a meta-analysis, Wood et al. reported that ablation and pacing therapy in chronic refractory AF can significantly improve quality of life w18x. Controlled regular ventricular rate provided by pacing might contribute to this improvement. Clark et al. w19x reported an acute pacing study in patients after atrioventricular nodal (AVN) ablation. Pacing with a regular rate in the VVI mode at the average rate of AF resulted in higher cardiac output than pacing at the same rate and rhythm in the VVT mode triggered to the RR intervals present in AF. Daoud et al. w20x reported that cardiac output was higher with regular vs irregular right ventricular apical pacing at two paced sites in patients after AVN ablation. Irregular ventricular rate in AF may influence preload, afterload, or inotropic state in turn affecting ventricular performance. The marked beat-to-beat variability in the intensity of pulse and blood pressures is due to changes in LV contractility, according to Frank Starling mechanism w21x. Postextrasystolic potentiation occurs following a short long RR sequence w22x. In heart failure patients, this beat-to-beat variability in LV contractility may have deleterious effects by further exacerbating increases in sympathetictone and salt and water retention present as compensatory responses. These physiological changes may explain why heart failure patients in AF have more symptoms and worse exercise capacity. However, there are conflicting results in terms of any difference in exercise tolerance between the AF and SR groups. In the V-HeFT I w14x study using vasodilator therapy, peak oxygen capacity was similar in both the AF and SR groups. In the V-HeFT II study w15x, there was no difference in change in peak oxygen consumption during the first 2 years but patients with AF showed a decline at 2.5 years. Data on beta-blocker therapy in patients with AF or SR in terms of exercise capacity is limited. Our study may contribute to this information. In patients with dilated cardiomyopathy, restrictive filling pattern with short mitral E deceleration time was associated with worse prognosis w23 25x. Prolongation of mitral E deceleration time in both groups by betablocker reflected an improvement in diastolic function and possibly might have an impact on survival improvement. There is controversy about the choice and doses of beta-blocker in patients with heart failure. Gilbert et al. w26x reported that carvedilol may be associated with greater improvement in NYHA functional class. In our previous double blind-randomized study w5x, both metoprolol and carvedilol were equally effective in improving LV ejection fraction, quality of life and exercise capacity. The observed difference between SR and AF groups in this study is probably independent of the choice of betablocker. The dose (50 mgyd) of carvedilol in the current study was comparable to the mean dose (44 49 mgyd) of this drug used in the multicentre trials w1,2,27x showing a reduction in morbidity and mortality in patients with heart failure. The dose (100 mgyd) of metoprolol in this study was slightly lower than that in Metoprolol in Dilated Cardiomyopathy Trial (108 mgy d) w28x. In the MERIT-HF study w3,4x, slow-release form of metoprolol succinate was used and the adjusted equivalent dose of metoprolol tartrate was 119 mgyd.

494 J.W. Fung et al. / The European Journal of Heart Failure 4 (2002) 489 494 4.1. Study limitations This study had a relatively small number of patients, especially in the AF group, and there is a possibility of a type II error. It was not powered to detect any differences in mortality and was designed to determine if there were any obvious or major differences in clinical efficacy, especially in terms of symptoms, quality of life and exercise capacity between the SR and AF groups. To this end, we used a wide range of well-validated techniques including the Minnesota Heart Failure Symptom Questionnaire and the 6-min walk test. Several studies have now demonstrated a clear independent inverse relation between the 6-min walk test and both mortality and morbidity w29x. 5. Conclusion In this study, we have confirmed the beneficial effects of the beta-blockers metoprolol and carvedilol, in improving LV ejection fraction in chronic heart failure patients, in either SR or AF. However, the improvement in exercise capacity and quality of life by beta-blocker therapy, could only be observed in patients in SR. References w1x Packer M, Coats AJS, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N. Engl. J. Med. 2001;344:1651 8. w2x Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N. Engl. J. Med. 1996;334:1349 55. w3x MERIT-HF Study Group, Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the metoprolol CRyXL randomized intervention trial in congestive heart failure (MERIT-HF). JAMA 2000;283:1295 302. w4x MERIT-HF Study Group. Effects of metoprolol CRyXL in chronic heart failure: metoprolol CRyXL randomized intervention trial in congestive heart failure (MERIT-HF). Lancet 1999;353:2001 7. w5x Sanderson JE, Chan SKW, Yip G, et al. Beta-Blockade in heart failure. A comparison of carvedilol with metoprolol. J. Am. Coll. Cardiol. 1999;34:1522 8. w6x Carson PE, Johnson GR, Dunkman WB, et al. The influence of atrial fibrillation on prognosis in mild to moderate heart failure. Circulation 1993;87(Suppl. VI):VI-102 VI-110. w7x Doval HC, Nul DR, Grancelli HO, et al. Randomized trial of low-dose amiodarone in severe congestive heart failure. Lancet 1994;334:493 8. w8x Singh SN, Fletcher RD, Fisher SG, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. N. Engl. J. Med. 1995;333:77 82. w9x Lechat P, Packer M, Chalon S, et al. Clinical effects of b- adrenergic blockade in chronic heart failure. A meta-analysis of double-blind placebo-controlled, randomized trials. Circulation 1998;98:1184 91. w10x Cleland JGF, Bristow EE, Remmes WY, et al. Beta blocking agents in heart failure. Should they be used? Eur. Heart J. 1996;17:1629 39. w11x Narayan SM, Cain ME, Smith JM. Atrial fibrillation. Lancet 1997;350:943 50. w12x Sanderson JE, Chan SKW, Yu CM, et al. b-blockers in heart failure: a comparison of a vasodilating b-blocker with metoprolol. Heart 1998;79:86 92. w13x Cohen GJ, Pietrolungo JF, Thomas JD, et al. A practical guide to assessment of ventricular diastolic function using Doppler echocardiography. J. Am. Coll. Cardiol. 1996;27:1753 60. w14x Cohn JN, Archibald DG, Ziesche S, et al. Effect of therapy on mortality in chronic congestive heart failure: a result of Veterans Administration Cooperative Study (V-HeFT). N. Engl. J. Med. 1986;314:1547 52. w15x Cohn JN, Johnson G, Ziesches S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N. Engl. J. Med. 1991;325:303 10. w16x Joglar JA, Acusta AP, Shusterman NH, et al. Effect of carvedilol on survival and hemodynamics in patients with atrial fibrillation and left ventricular dysfunction: retrospective analysis of the US Carvedilol Heart Failure Trials Program. Am. Heart J. 2001;142:498 501. w17x Lechat P, Hulot JS, Escolano S, et al. Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II Trial. Circulation 2001;103:1428 33. w18x Wood MA, Brown-Mahoney C, Kay GN, et al. Clinical outcomes after ablation and pacing therapy for atrial fibrillation: a meta-analysis. Circulation 2000;101:1138 44. w19x Clark DM, Plumb VJ, Kay GN. The hemodynamics of atrial fibrillation: the independent effect of an irregular RR interval. Circulation 1995;95:I 141 (Abstract). w20x Daoud E, Weiss R, Bahu M, et al. Effect of a regular and irregular ventricular rhythm on cardiac output. PACE 1996;19:691 (Abstract). w21x Noble MIM. The Frank-Starling curve. Clin. Sci. Mol. Med. 1978;54:1 7. w22x Hard SMC, Noble MIM, Seed WA. Postextrasystolicpotentiation and its contribution to the beat-to-beat variation of the pulse during atrial fibrillation. Circulation 1992;86:1223 32. w23x Rihal CS, Nishimura RA, Hatle LK, Bailey KR, Tajik AJ. Systolic and diastolic dysfunction in patients with clinical diagnosis of dilated cardiomyopathy. Relation to symptoms and prognosis. Circulation 1994;90:2772 9. w24x Little WC, Ohno M, Kitzman DW, Thomas JD, Cheng CP. Determination of left ventricular chamber stiffness from the time of deceleration of early ventricular filling. Circulation 1995;92:1933 9. w25x Sanderson JE, Yeung LY, Chan S, et al. Effect of b-blockade on baroreceptor and autonomic function in heart failure. Clin. Sci. 1999;96:137 46. w26x Gilbert EM, Abraham WT, Olsen S, et al. Comparative hemodynamic, left ventricular functional, and anti-adrenergic effects of chronic treatment with metoprolol versus carvedilol in the failing heart. Circulation 1996;94:2817 25. w27x Australia New Zealand Heart Failure Research Collaborative Group. Randomized placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischemic heart disease. Lancet 1997;349:375 80. w28x Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group, Waagstein F, Bristow MR, Swedberg K, et al. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet 1993;342:1441 6. w29x Yusuf S, Tsuyuki R. Using exercise endpoints in heart failure trials: design considerations. Eur. Heart J. 1996;17:4 6.