- Email: [email protected]
Use of cardiac resynchronization therapy to optimize beta-blocker therapy in patients with heart failure and prolonged QRS duration
12. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651–1658. 13. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996;334:1349 –1355. 14. Anker SD, Egerer KR, Volk HD, Kox WJ, Poole-Wilson PA, Coats AJS. Elevated soluble CD14 receptors and altered cytokines in chronic heart failure. Am J Cardiol 1997;79:1426 –1430. 15. Anker SD, von Haehling S. Inflammatory mediators in chronic heart failure: an overview. Heart 2004;90:464 – 470.
16. von Haehling S, Jankowska EA, Anker SD. Tumour necrosis factor-a and the
failing heart: pathophysiology and therapeutic implications. Basic Res Cardiol 2004;99:18 –28. 17. Brixius K, Bundkirchen A, Bolck B, Mehlhorn U, Schwinger RH. Nebivolol, bucindolol, metoprolol and carvedilol are devoid of intrinsic sympathomimetic activity in human myocardium. Br J Pharmacol 2001;133:1330 –1338. 18. Genth-Zotz S, von Haehling S, Bolger AP, Kalra PR, Wensel R, Coats AJS, Anker SD. Pathophysiological quantities of endotoxin induce tumor necrosis factor release in whole blood from patients with chronic heart failure. Am J Cardiol 2002;90:1226 –1230. 19. Tohmeh JF, Cryer PE. Biphasic adrenergic modulation of beta-adrenergic receptors in man. Agonist-induced early increment and late decrement in betaadrenergic receptor number. J Clin Invest 1980;65:836 – 840.
Use of Cardiac Resynchronization Therapy to Optimize Beta-Blocker Therapy in Patients With Heart Failure and Prolonged QRS Duration Juan M. Aranda, Jr., MD, Gregory W. Woo, MD, Jamie B. Conti, MD, Richard S. Schofield, MD, C. Richard Conti, MD, and James A. Hill, MD A retrospective analysis was performed on 52 patients with heart failure to determine the change in -blocker therapy after cardiac resynchronization therapy (CRT). After 6 months of CRT, the number of patients receiving -blocker therapy increased from 36 to 44, with improved clinical outcomes and larger -blocker doses, indicating that these 2 therapies may work together to improve outcomes by allowing the use of larger doses of  blockers while correcting ventricular dyssynchrony. 䊚2005 by Excerpta Medica Inc. (Am J Cardiol 2005;95:889 – 891)
harmacologic therapy with  blockers has had a dramatic impact on heart failure (HF) management, P with proved reductions in mortality, sudden death, and hospitalization.1– 6 Despite these established benefits, the use of -blocker therapy in recent randomized clinical HF trials ranges from only 30% to 60%.7,8 Factors that cause physicians to hesitate starting -blocker therapy or increasing -blocker doses include worsening HF, hypotension, and bradycardia.9 Cardiac resynchronization therapy (CRT) improves New York Heart Association functional class, exercise capacity, and quality of life while reducing hospitalizations in patients with HF and prolonged QRS duration.8,10 The hemodynamic effects of CRT beyond the pacing of ventricles and decreasing dyssynchrony include increasing blood pressure, increasing cardiac output, and reducing pulmonary capillary wedge pressure.10,11 Most of the clinical problems for which -blocker therapy is abandoned or not aggressively pursued are potentially stabilized with CRT. From the Division of Cardiovascular Medicine, University of Florida College of Medicine, Gainesville, Florida. Dr. Aranda’s address is: University of Florida College of Medicine, Division of Cardiovascular Medicine, 1600 SW Archer Road, Room M421, Box 100277, Gainesville, Florida 32610-0277. E-mail: [email protected]. ufl.edu. Manuscript received September 22, 2004; revised manuscript received and accepted December 6, 2004. ©2005 by Excerpta Medica Inc. All rights reserved. The American Journal of Cardiology Vol. 95 April 1, 2005
Treatment changes in -blocker therapy after CRT are not known. The purpose of this retrospective analysis was to determine whether CRT allows the optimization of -blocker therapy in patients with HF and whether it facilitates the addition of -blocker therapy in patients with HF who were previously intolerant of it. •••
We performed a retrospective analysis of all patients with HF and prolonged QRS duration who received CRT at the University of Florida from July 2001 to June 2003. Patients were included in the study if they had successful CRT device implantations and ⱖ6 months of follow-up data, including functional class, ejection fraction, peak oxygen consumption evaluation, or measurements of left ventricular enddiastolic dimensions. We used descriptive statistics to analyze baseline demographics and paired-sample t tests to compare -blocker therapy and doses before and after the initiation of CRT. Microsoft Excel (Microsoft Corporation, Redmond, Washington) software was used to perform the statistical calculations. A p value ⬍0.05 was considered significant. From July 2001 to July 2003, 60 patients with HF and prolonged QRS duration underwent CRT at the University of Florida. Eight of those patients were excluded from this analysis because of sudden death (n ⫽ 4) or the need for cardiac transplantation ⱕ6 months after receiving CRT (n ⫽ 4) (Figure 1). The patients excluded because of sudden death did not have cardiac defibrillators, whereas the patients who were excluded because of cardiac transplantation were receiving angiotensin-converting enzyme inhibitors and -blocker therapy. Thus, 52 patients with HF, prolonged QRS duration, successful CRT device implantation, and ⱖ6 months of follow-up data were considered for this analysis. Table 1 lists the baseline demographics of this patient population. Our population of patients with HF receiving CRT reflects the 0002-9149/05/$–see front matter doi:10.1016/j.amjcard.2004.12.023
889
FIGURE 1. Algorithm describing outcomes of patients considered for this analysis. TABLE 1 Baseline Demographics of Patients With HF Who Underwent CRT Patient Characteristic (n ⫽ 52) Ischemic cardiomyopathy Nonischemic cardiomyopathy Men Hypertension Diabetes mellitus Mean age (yrs) New York Heart Association functional class Ejection fraction (%) Left ventricular end-diastolic dimension (mm) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats/min)
n (%) 27 (52%) 25 (48%) 30 (58%) 19 (37%) 14 (27%) 63 ⫾ 10 3 ⫾ 0.5 18 ⫾ 6 71 ⫾ 12 113 ⫾ 19 63 ⫾ 19 77 ⫾ 14
of metoprolol succinate was 81.3 ⫾ 37 mg, and the average daily dose of carvedilol was 25 ⫾ 12 mg. For the entire cohort of 52 patients, there was a decrease in New York Heart Association functional class (3.1 ⫾ 0.5 before CRT vs 2.5 ⫾ 0.6 after CRT, p ⬍0.01), an increase in ejection fraction (18 ⫾ 5% before CRT vs 24.8 ⫾ 12% after CRT, p ⫽ 0.09), an increase in peak oxygen consumption (12.2 ⫾ 3 before CRT vs 14.9 ⫾ 4.1 cm3 · kg⫺1 · min⫺1 after CRT, p ⫽ 0.02), and a reduction in left ventricular end-diastolic dimensions (72 ⫾ 13 before CRT vs 65 ⫾ 15.1 mm after CRT, p ⬍0.001). Patients who had an increase in -blocker therapy with CRT had a greater improvement in functional class and a greater reduction in left ventricular end-diastolic dimensions than patients with no change in -blocker therapy after CRT (Table 3). Overall blood pressure and heart rate did not change with the addition or titration of -blocker therapy after CRT (113 ⫾ 19/63 ⫾ 10 at baseline vs 114 ⫾ 20/64 ⫾ 10 mm Hg after CRT, p ⫽ NS; 77 ⫾ 14 at baseline vs 76 ⫾ 14 beats/min after CRT, p ⫽ NS). •••
The results of this retrospective analysis demonstrate that -blocker therapy can be increased in patients with HF receiving CRT. Furthermore, in some patients who are intolerant of -blocker therapy, CRT allows the reinitiation of -blocker therapy with reasonable success. Randomized HF trials have reported increased survival and reduced need for hospitalizations for worsening HF with  blockers in a broad spectrum of patients with systolic HF in New York Heart Association TABLE 2 Changes in -blocker Therapy After CRT functional classes II to IV. In these trials, treatment was initiated with a Before CRT After CRT small -blocker dose with slow titraTherapy n (%) ADD (mg) n (%) ADD (mg) p Value* tion to a predefined maximum target All -blockers 36 (69) 44 (85) 0.03 dose or to the largest dose tolerated. Metoprolol CR/XL 10 (19) 73.4 ⫾ 67 14 (27) 90.6 ⫾ 38 0.06 None of the trials was designed as a Carvedilol 26 (50) 24.7 ⫾ 20 30 (58) 25.7 ⫾ 22 0.26 dose-response study. *Represents change in ADD before and after CRT. Several questions should be asked ADD ⫽ average daily dose. relating to dose responses to -blocker therapy. Do larger doses of  blockers offer greater reductions in mortypical patient population enrolled in national CRT tality and hospitalization than smaller doses? Do patients need to reach clinical trial target doses of clinical trials. Table 2 lists the changes in -blocker therapy after -blocker therapy to receive benefit? Some group CRT. After a mean follow-up of 11 ⫾ 5 months, the analyses suggest that larger doses of -blocker theruse of -blocker therapy increased from 69% to 85% apy are associated with better clinical outcomes. Wik(p ⫽ 0.03). The average daily dose of metoprolol strand and colleagues9 performed a post hoc subgroup succinate increased, whereas the average daily dose of analysis in the Metoprolol CR/XL Randomized Intercarvedilol did not change. vention Trial in Congestive Heart Failure, with the There were 16 patients (31%) in the analysis who, goal of reporting clinical outcomes in 2 dosage subat the time of the initiation of CRT, were not receiving groups: 1 that had reached ⬎100 mg of metoprolol -blocker therapy. Reasons for intolerance of CR/XL once daily (large-dose group, n ⫽ 1,202, mean -blocker therapy in this group of patients included 192 mg) and 1 that reached ⱕ100 mg (small-dose symptomatic hypotension (n ⫽ 4), symptomatic bra- group, n ⫽ 412, mean 76 mg). Mortality tended to be dycardia (n ⫽ 5), and worsening HF (n ⫽ 7) docu- greater in the small-dose metoprolol CR/XL subgroup mented by their primary care physicians. Eight of than in the large-dose subgroup (8.0% vs 6.2%, relathese patients were able to start -blocker therapy tive risk 1.30, 95% confidence interval 0.87 to 1.96). after CRT. In these 8 patients, the average daily dose However, relative mortality risk reduction (Cox ad890 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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TABLE 3 Change in Functional Class, Ejection Fraction, Left Ventricular End-diastolic Dimension, and Peak Oxygen Consumption According to Change in -blocker Dose After CRT Increase in -blocker Therapy Variable New York Heart Association functional class Ejection fraction Left ventricular end-diastolic dimension (mm) Peak oxygen consumption (ml3 · kg⫺1 · min⫺1)
Before
After
No increase in -blocker Therapy
% Change
p Value*
Before
2.9 ⫾ 0.5
2.2 ⫾ 0.5
24% 2
0.003
3.1 ⫾ 0.5
18 ⫾ 4% 81 ⫾ 13
22 ⫾ 7% 71 ⫾ 19
22% 1 12% 2
0.199 0.019
19 ⫾ 7% 68 ⫾ 11
23% 1
0.10
13.6 ⫾ 4
16.7 ⫾ 4
12.6 ⫾ 2
After
% Change
p Value†
2.6 ⫾ 0.6
16% 2
0.0001
32% 1 6% 2
0.07 0.008
25 ⫾ 17% 64 ⫾ 12 13.4 ⫾ 4
6% 1
0.73
*Comparison of end points before and after CRT in patients who had an increase in -blocker therapy. † Comparison of end points before and after CRT in patients who had no increase in -blocker therapy.
justed) with metoprolol CR/XL compared with placebo (n ⫽ 1,845) was similar: 38% (95% confidence interval 11 to 57) in the small-dose subgroup (p ⫽ 0.010) and 38% (95% confidence interval 16 to 55) in the large-dose subgroup (p ⫽ 0.0022). Why are so many patients with HF denied -blocker therapy or not receiving maximum study doses? Reasons for smaller than expected doses of -blocker therapy vary. Wikstrand et al9 demonstrated that reasons for smaller doses of metoprolol CR/XL in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure included low heart rate (10.4%), low blood pressure (5.4%), and symptoms of worsening HF (6.7%). Low heart rate was the most common reason stated in the -blocker therapy group. CRT can potentially mitigate side effects that -blocker therapy may create in the treatment of HF. When lower rate circuits are provided with pacing, bradycardia is no longer a problem for -blocker therapy. The Comparison of Medical Therapy, Pacing, and Defibrillation Trial in Heart Failure recently demonstrated that systolic blood pressure increased with CRT.10 This explains why in our patient population, -blocker therapy increased with no significant change in blood pressure. The American College of Cardiology/American Heart Association/North American Society of Pacing and Electrophysiology pacing guidelines state that the criteria for CRT are refractory class III or IV HF symptoms despite maximum medical therapy, which includes angiotensin-converting enzyme inhibitors and  blockers in patients with QRS duration ⱖ130 ms.12 If patients meet these criteria and receive CRT, this presents a unique opportunity to further optimize -blocker therapy. This is an important observation in view of the recently published Comparison of Medical Therapy, Pacing, and Defibrillation Trial in Heart Failure results that showed greater reductions in hospitalization and mortality in patients receiving CRT and -blocker therapy than in patients receiving CRT and no -blocker therapy.10 Our analysis demonstrates that -blocker therapy can be further optimized in patients who receive CRT. CRT may allow the reinitiation of -blocker therapy in those patients who were previously intolerant of  blockers. CRT should not be used to replace standard
therapy but to augment it when primary therapy with angiotensin-converting enzyme inhibitors,  blockers, and aldosterone blockade has not fully reversed symptoms. 1. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure:
Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001–2007. 2. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9 –13. 3. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651–1658. 4. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996;334:1349 –1355. 5. Fowler MB, Vera-Llonch M, Oster G, Bristow MR, Cohn JN, Colucci WS, Gilbert EM, Lukas MA, Lacey MJ, Richner R, et al. Influence of carvedilol on hospitalizations in heart failure: incidence, resource utilization and costs. U.S. Carvedilol Heart Failure Study Group. J Am Coll Cardiol 2001;37:1692– 1699. 6. Waagstein F, Bristow MR, Swedberg K, Camerini F, Fowler MB, Silver MA, Gilbert EM, Johnson MR, Goss FG, Hjalmarson A. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Lancet 1993;342:1441–1446. 7. Cohn JN, Tognoni G, Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667–1675. 8. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, et al, MIRACLE Study Group. Multicenter InSync Randomized Clinical Evaluation. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–1853. 9. Wikstrand J, Hjalmarson A, Waagstein F, Fagerberg B, Goldstein S, Kjekshus J, Wedel H, MERIT-HF Study Group. Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure: analysis of the experience in Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF). J Am Coll Cardiol 2002;40:491– 498. 10. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, DeMarco T, Carson P, DiCarlo L, DeMets D, White BG, et al, Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced heart failure. N Engl J Med 2004;350:2140 –2150. 11. Leclerq C, Cazeau S, Le Breton H, Ritter P, Mabo P, Gras D, Pavin D, Lazarus A, Daubert JC. Acute hemodynamic effects of biventricular DDD pacing in patients with end-stage heart failure. J Am Coll Cardiol 1998;32: 1825–1831. 12. Gregoratos G, Abrams J, Epstein AE, Freedman RA, Hayes DL, Hlatky MA, Kerber RE, Naccerelli GV, Schoenfeld MH, Silka MJ, et al, American College of Cardiology/American Heart Association Task Force on Practice Guidelines/North American Society for Pacing and Electrophysiology Committee to Update the 1998 Pacemaker Guidelines. ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: summary article: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (ACC/AHA/ NASPE Committee to Update the 1998 Pacemaker Guidelines). Circulation 2002;106:2145–2161.
BRIEF REPORTS
891
16. von Haehling S, Jankowska EA, Anker SD. Tumour necrosis factor-a and the
failing heart: pathophysiology and therapeutic implications. Basic Res Cardiol 2004;99:18 –28. 17. Brixius K, Bundkirchen A, Bolck B, Mehlhorn U, Schwinger RH. Nebivolol, bucindolol, metoprolol and carvedilol are devoid of intrinsic sympathomimetic activity in human myocardium. Br J Pharmacol 2001;133:1330 –1338. 18. Genth-Zotz S, von Haehling S, Bolger AP, Kalra PR, Wensel R, Coats AJS, Anker SD. Pathophysiological quantities of endotoxin induce tumor necrosis factor release in whole blood from patients with chronic heart failure. Am J Cardiol 2002;90:1226 –1230. 19. Tohmeh JF, Cryer PE. Biphasic adrenergic modulation of beta-adrenergic receptors in man. Agonist-induced early increment and late decrement in betaadrenergic receptor number. J Clin Invest 1980;65:836 – 840.
Use of Cardiac Resynchronization Therapy to Optimize Beta-Blocker Therapy in Patients With Heart Failure and Prolonged QRS Duration Juan M. Aranda, Jr., MD, Gregory W. Woo, MD, Jamie B. Conti, MD, Richard S. Schofield, MD, C. Richard Conti, MD, and James A. Hill, MD A retrospective analysis was performed on 52 patients with heart failure to determine the change in -blocker therapy after cardiac resynchronization therapy (CRT). After 6 months of CRT, the number of patients receiving -blocker therapy increased from 36 to 44, with improved clinical outcomes and larger -blocker doses, indicating that these 2 therapies may work together to improve outcomes by allowing the use of larger doses of  blockers while correcting ventricular dyssynchrony. 䊚2005 by Excerpta Medica Inc. (Am J Cardiol 2005;95:889 – 891)
harmacologic therapy with  blockers has had a dramatic impact on heart failure (HF) management, P with proved reductions in mortality, sudden death, and hospitalization.1– 6 Despite these established benefits, the use of -blocker therapy in recent randomized clinical HF trials ranges from only 30% to 60%.7,8 Factors that cause physicians to hesitate starting -blocker therapy or increasing -blocker doses include worsening HF, hypotension, and bradycardia.9 Cardiac resynchronization therapy (CRT) improves New York Heart Association functional class, exercise capacity, and quality of life while reducing hospitalizations in patients with HF and prolonged QRS duration.8,10 The hemodynamic effects of CRT beyond the pacing of ventricles and decreasing dyssynchrony include increasing blood pressure, increasing cardiac output, and reducing pulmonary capillary wedge pressure.10,11 Most of the clinical problems for which -blocker therapy is abandoned or not aggressively pursued are potentially stabilized with CRT. From the Division of Cardiovascular Medicine, University of Florida College of Medicine, Gainesville, Florida. Dr. Aranda’s address is: University of Florida College of Medicine, Division of Cardiovascular Medicine, 1600 SW Archer Road, Room M421, Box 100277, Gainesville, Florida 32610-0277. E-mail: [email protected]. ufl.edu. Manuscript received September 22, 2004; revised manuscript received and accepted December 6, 2004. ©2005 by Excerpta Medica Inc. All rights reserved. The American Journal of Cardiology Vol. 95 April 1, 2005
Treatment changes in -blocker therapy after CRT are not known. The purpose of this retrospective analysis was to determine whether CRT allows the optimization of -blocker therapy in patients with HF and whether it facilitates the addition of -blocker therapy in patients with HF who were previously intolerant of it. •••
We performed a retrospective analysis of all patients with HF and prolonged QRS duration who received CRT at the University of Florida from July 2001 to June 2003. Patients were included in the study if they had successful CRT device implantations and ⱖ6 months of follow-up data, including functional class, ejection fraction, peak oxygen consumption evaluation, or measurements of left ventricular enddiastolic dimensions. We used descriptive statistics to analyze baseline demographics and paired-sample t tests to compare -blocker therapy and doses before and after the initiation of CRT. Microsoft Excel (Microsoft Corporation, Redmond, Washington) software was used to perform the statistical calculations. A p value ⬍0.05 was considered significant. From July 2001 to July 2003, 60 patients with HF and prolonged QRS duration underwent CRT at the University of Florida. Eight of those patients were excluded from this analysis because of sudden death (n ⫽ 4) or the need for cardiac transplantation ⱕ6 months after receiving CRT (n ⫽ 4) (Figure 1). The patients excluded because of sudden death did not have cardiac defibrillators, whereas the patients who were excluded because of cardiac transplantation were receiving angiotensin-converting enzyme inhibitors and -blocker therapy. Thus, 52 patients with HF, prolonged QRS duration, successful CRT device implantation, and ⱖ6 months of follow-up data were considered for this analysis. Table 1 lists the baseline demographics of this patient population. Our population of patients with HF receiving CRT reflects the 0002-9149/05/$–see front matter doi:10.1016/j.amjcard.2004.12.023
889
FIGURE 1. Algorithm describing outcomes of patients considered for this analysis. TABLE 1 Baseline Demographics of Patients With HF Who Underwent CRT Patient Characteristic (n ⫽ 52) Ischemic cardiomyopathy Nonischemic cardiomyopathy Men Hypertension Diabetes mellitus Mean age (yrs) New York Heart Association functional class Ejection fraction (%) Left ventricular end-diastolic dimension (mm) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats/min)
n (%) 27 (52%) 25 (48%) 30 (58%) 19 (37%) 14 (27%) 63 ⫾ 10 3 ⫾ 0.5 18 ⫾ 6 71 ⫾ 12 113 ⫾ 19 63 ⫾ 19 77 ⫾ 14
of metoprolol succinate was 81.3 ⫾ 37 mg, and the average daily dose of carvedilol was 25 ⫾ 12 mg. For the entire cohort of 52 patients, there was a decrease in New York Heart Association functional class (3.1 ⫾ 0.5 before CRT vs 2.5 ⫾ 0.6 after CRT, p ⬍0.01), an increase in ejection fraction (18 ⫾ 5% before CRT vs 24.8 ⫾ 12% after CRT, p ⫽ 0.09), an increase in peak oxygen consumption (12.2 ⫾ 3 before CRT vs 14.9 ⫾ 4.1 cm3 · kg⫺1 · min⫺1 after CRT, p ⫽ 0.02), and a reduction in left ventricular end-diastolic dimensions (72 ⫾ 13 before CRT vs 65 ⫾ 15.1 mm after CRT, p ⬍0.001). Patients who had an increase in -blocker therapy with CRT had a greater improvement in functional class and a greater reduction in left ventricular end-diastolic dimensions than patients with no change in -blocker therapy after CRT (Table 3). Overall blood pressure and heart rate did not change with the addition or titration of -blocker therapy after CRT (113 ⫾ 19/63 ⫾ 10 at baseline vs 114 ⫾ 20/64 ⫾ 10 mm Hg after CRT, p ⫽ NS; 77 ⫾ 14 at baseline vs 76 ⫾ 14 beats/min after CRT, p ⫽ NS). •••
The results of this retrospective analysis demonstrate that -blocker therapy can be increased in patients with HF receiving CRT. Furthermore, in some patients who are intolerant of -blocker therapy, CRT allows the reinitiation of -blocker therapy with reasonable success. Randomized HF trials have reported increased survival and reduced need for hospitalizations for worsening HF with  blockers in a broad spectrum of patients with systolic HF in New York Heart Association TABLE 2 Changes in -blocker Therapy After CRT functional classes II to IV. In these trials, treatment was initiated with a Before CRT After CRT small -blocker dose with slow titraTherapy n (%) ADD (mg) n (%) ADD (mg) p Value* tion to a predefined maximum target All -blockers 36 (69) 44 (85) 0.03 dose or to the largest dose tolerated. Metoprolol CR/XL 10 (19) 73.4 ⫾ 67 14 (27) 90.6 ⫾ 38 0.06 None of the trials was designed as a Carvedilol 26 (50) 24.7 ⫾ 20 30 (58) 25.7 ⫾ 22 0.26 dose-response study. *Represents change in ADD before and after CRT. Several questions should be asked ADD ⫽ average daily dose. relating to dose responses to -blocker therapy. Do larger doses of  blockers offer greater reductions in mortypical patient population enrolled in national CRT tality and hospitalization than smaller doses? Do patients need to reach clinical trial target doses of clinical trials. Table 2 lists the changes in -blocker therapy after -blocker therapy to receive benefit? Some group CRT. After a mean follow-up of 11 ⫾ 5 months, the analyses suggest that larger doses of -blocker theruse of -blocker therapy increased from 69% to 85% apy are associated with better clinical outcomes. Wik(p ⫽ 0.03). The average daily dose of metoprolol strand and colleagues9 performed a post hoc subgroup succinate increased, whereas the average daily dose of analysis in the Metoprolol CR/XL Randomized Intercarvedilol did not change. vention Trial in Congestive Heart Failure, with the There were 16 patients (31%) in the analysis who, goal of reporting clinical outcomes in 2 dosage subat the time of the initiation of CRT, were not receiving groups: 1 that had reached ⬎100 mg of metoprolol -blocker therapy. Reasons for intolerance of CR/XL once daily (large-dose group, n ⫽ 1,202, mean -blocker therapy in this group of patients included 192 mg) and 1 that reached ⱕ100 mg (small-dose symptomatic hypotension (n ⫽ 4), symptomatic bra- group, n ⫽ 412, mean 76 mg). Mortality tended to be dycardia (n ⫽ 5), and worsening HF (n ⫽ 7) docu- greater in the small-dose metoprolol CR/XL subgroup mented by their primary care physicians. Eight of than in the large-dose subgroup (8.0% vs 6.2%, relathese patients were able to start -blocker therapy tive risk 1.30, 95% confidence interval 0.87 to 1.96). after CRT. In these 8 patients, the average daily dose However, relative mortality risk reduction (Cox ad890 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 95
APRIL 1, 2005
TABLE 3 Change in Functional Class, Ejection Fraction, Left Ventricular End-diastolic Dimension, and Peak Oxygen Consumption According to Change in -blocker Dose After CRT Increase in -blocker Therapy Variable New York Heart Association functional class Ejection fraction Left ventricular end-diastolic dimension (mm) Peak oxygen consumption (ml3 · kg⫺1 · min⫺1)
Before
After
No increase in -blocker Therapy
% Change
p Value*
Before
2.9 ⫾ 0.5
2.2 ⫾ 0.5
24% 2
0.003
3.1 ⫾ 0.5
18 ⫾ 4% 81 ⫾ 13
22 ⫾ 7% 71 ⫾ 19
22% 1 12% 2
0.199 0.019
19 ⫾ 7% 68 ⫾ 11
23% 1
0.10
13.6 ⫾ 4
16.7 ⫾ 4
12.6 ⫾ 2
After
% Change
p Value†
2.6 ⫾ 0.6
16% 2
0.0001
32% 1 6% 2
0.07 0.008
25 ⫾ 17% 64 ⫾ 12 13.4 ⫾ 4
6% 1
0.73
*Comparison of end points before and after CRT in patients who had an increase in -blocker therapy. † Comparison of end points before and after CRT in patients who had no increase in -blocker therapy.
justed) with metoprolol CR/XL compared with placebo (n ⫽ 1,845) was similar: 38% (95% confidence interval 11 to 57) in the small-dose subgroup (p ⫽ 0.010) and 38% (95% confidence interval 16 to 55) in the large-dose subgroup (p ⫽ 0.0022). Why are so many patients with HF denied -blocker therapy or not receiving maximum study doses? Reasons for smaller than expected doses of -blocker therapy vary. Wikstrand et al9 demonstrated that reasons for smaller doses of metoprolol CR/XL in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure included low heart rate (10.4%), low blood pressure (5.4%), and symptoms of worsening HF (6.7%). Low heart rate was the most common reason stated in the -blocker therapy group. CRT can potentially mitigate side effects that -blocker therapy may create in the treatment of HF. When lower rate circuits are provided with pacing, bradycardia is no longer a problem for -blocker therapy. The Comparison of Medical Therapy, Pacing, and Defibrillation Trial in Heart Failure recently demonstrated that systolic blood pressure increased with CRT.10 This explains why in our patient population, -blocker therapy increased with no significant change in blood pressure. The American College of Cardiology/American Heart Association/North American Society of Pacing and Electrophysiology pacing guidelines state that the criteria for CRT are refractory class III or IV HF symptoms despite maximum medical therapy, which includes angiotensin-converting enzyme inhibitors and  blockers in patients with QRS duration ⱖ130 ms.12 If patients meet these criteria and receive CRT, this presents a unique opportunity to further optimize -blocker therapy. This is an important observation in view of the recently published Comparison of Medical Therapy, Pacing, and Defibrillation Trial in Heart Failure results that showed greater reductions in hospitalization and mortality in patients receiving CRT and -blocker therapy than in patients receiving CRT and no -blocker therapy.10 Our analysis demonstrates that -blocker therapy can be further optimized in patients who receive CRT. CRT may allow the reinitiation of -blocker therapy in those patients who were previously intolerant of  blockers. CRT should not be used to replace standard
therapy but to augment it when primary therapy with angiotensin-converting enzyme inhibitors,  blockers, and aldosterone blockade has not fully reversed symptoms. 1. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure:
Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001–2007. 2. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9 –13. 3. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651–1658. 4. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996;334:1349 –1355. 5. Fowler MB, Vera-Llonch M, Oster G, Bristow MR, Cohn JN, Colucci WS, Gilbert EM, Lukas MA, Lacey MJ, Richner R, et al. Influence of carvedilol on hospitalizations in heart failure: incidence, resource utilization and costs. U.S. Carvedilol Heart Failure Study Group. J Am Coll Cardiol 2001;37:1692– 1699. 6. Waagstein F, Bristow MR, Swedberg K, Camerini F, Fowler MB, Silver MA, Gilbert EM, Johnson MR, Goss FG, Hjalmarson A. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Lancet 1993;342:1441–1446. 7. Cohn JN, Tognoni G, Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667–1675. 8. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, et al, MIRACLE Study Group. Multicenter InSync Randomized Clinical Evaluation. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–1853. 9. Wikstrand J, Hjalmarson A, Waagstein F, Fagerberg B, Goldstein S, Kjekshus J, Wedel H, MERIT-HF Study Group. Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure: analysis of the experience in Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF). J Am Coll Cardiol 2002;40:491– 498. 10. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, DeMarco T, Carson P, DiCarlo L, DeMets D, White BG, et al, Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced heart failure. N Engl J Med 2004;350:2140 –2150. 11. Leclerq C, Cazeau S, Le Breton H, Ritter P, Mabo P, Gras D, Pavin D, Lazarus A, Daubert JC. Acute hemodynamic effects of biventricular DDD pacing in patients with end-stage heart failure. J Am Coll Cardiol 1998;32: 1825–1831. 12. Gregoratos G, Abrams J, Epstein AE, Freedman RA, Hayes DL, Hlatky MA, Kerber RE, Naccerelli GV, Schoenfeld MH, Silka MJ, et al, American College of Cardiology/American Heart Association Task Force on Practice Guidelines/North American Society for Pacing and Electrophysiology Committee to Update the 1998 Pacemaker Guidelines. ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: summary article: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (ACC/AHA/ NASPE Committee to Update the 1998 Pacemaker Guidelines). Circulation 2002;106:2145–2161.
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