American Journal of Therapeutics 0, 000000 (2011)

Effect of Carvedilol Versus Metoprolol CR/XL on Mortality in Patients With Heart Failure Treated With Cardiac Resynchronization Therapy: A COX Multivariate Regression Analysis
Xuedong Shen, MD,1 Chandra K. Nair, MD,1 Wilbert S. Aronow, MD,2* Tom Hee, MD,1 and Dennis J. Esterbrooks, MD1

We investigated in 136 consecutive patients with heart failure receiving cardiac resynchronization therapy (CRT) the effect of carvedilol versus metoprolol CR/XL versus no beta blocker on mortality. Of the 136 patients, 42 (31%) were on carvedilol, 80 (59%) were on metoprolol CR/XL, and 14 (10%) were not on a beta blocker. A decrease of left ventricular end-systolic volume $15% after CRT was dened as a positive response to CRT. Of the 136 patients, 62 (46%) responded to CRT. It was found that both carvedilol and metoprolol CR/XL were not related to CRT response on using Cox univariate regression analysis. Twenty-two of the 136 patients (16%) died during follow-up of 17 6 10 months after initiating CRT. Mortality occurred in 14 of 80 patients (18%) on metoprolol CR/XL, in 3 of 42 patients (7%) on carvedilol, and in 5 of 14 patients (36%) not on beta blockers (P = 0.04). After adjustment for age, gender, and the variables with signicant differences by Cox univariate regression, both carvedilol (hazard ratio = 0.14; P = 0.03; 95% condence interval = 0.020.86) and metoprolol CR/XL (hazard ratio = 0.19; P = 0.02; 95% condence interval = 0.040.80) were found to be related to mortality by Cox multivariate regression. Keywords: carvedilol, metoprolol CR/XL, cardiac resynchronization therapy, beta blockers, heart failure

INTRODUCTION
The American College of Cardiology/American Heart Association guidelines recommend using cardiac resynchronization therapy (CRT) in patients with heart failure, a left ventricular (LV) ejection fraction #35%, sinus rhythm, New York Heart Association (NYHA) class III, or ambulatory class IV symptoms despite
Cardiac Center of Creighton University School of Medicine, Omaha, NE; and 2Cardiology Division, Department of Medicine, New York Medical College, Valhalla, NY. Conict of interest: None. Funding source: None. *Address for correspondence: Cardiology Division, New York Medical College, Macy Pavilion, Room 138, Valhalla, NY 10595. E-mail: wsaronow@aol.com. 10752765 2011 Lippincott Williams & Wilkins
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recommended optimal medical therapy, and a QRS duration $120 milliseconds with a class I indication.1 Both carvedilol and metoprolol CR/XL reduce allcause mortality, cardiovascular mortality, sudden death, and death from worsening heart failure in patients with heart failure.2,3 However, the benet of carvedilol compared with metoprolol CR/XL in patients with heart failure receiving CRT needs to be investigated. Therefore, we investigated the effect of maximum tolerated dose of these drugs on CRT response and cardiac mortality in 136 consecutive patients with heart failure treated with CRT.

METHODS
We studied 136 consecutive patients with heart failure who were treated with CRT. The patients included 99
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Shen et al

men and 37 women, mean age 70 6 10 years. All 136 patients met the criteria for undergoing CRT with biventricular pacemaker implantation according to the American College of Cardiology/American Heart Association 2009 Guidelines,1 including an LV ejection fraction #35%, NYHA) class III or ambulatory IV heart failure, sinus rhythm, a QRS duration $120 milliseconds, and optimal medical therapy established before implantation. Of the 136 patients, 88 (65%) had ischemic heart disease (42 patients with previous myocardial infarction), and 48 had nonischemic heart disease. Of the 136 patients, 42 (31%) were treated with carvedilol (mean dose 21 6 15 mg/d) for 23 6 10 months after CRT, 80 (59%) were treated with metoprolol CR/XL (mean dose 63 6 53 mg/d) for 23 6 13 months after CRT, and 14 (10%) had contraindications to the use of beta blockers. After informed written consent was obtained, all 136 patients underwent CRT, and 135 (99%) were also implanted with a cardioverter debrillator in the cardiac electrophysiology laboratory. The LV lead was positioned into the lateral LV vein. The right ventricular (RV) debrillation lead was actively xated into the RV apex. The atrial pacing lead was xated into the high lateral right atrium. Conventional transthoracic echocardiography was performed with a Philips Sonos 7500 echocardiographic system and s3 transducer (Philips, Andover, MA). Baseline echocardiographic data before CRT and follow-up echocardiography after CRT were reviewed for all patients. The LV end-systolic volume, LV enddiastolic volume, LV ejection fraction, and left atrial volume were measured in apical views from the videotape or Philips Enconcert digital system according to the standard recommended by the American Society of Echocardiography.4 The end-systolic and end-diastolic ventricular dimensions were measured in the parasternal long-axis view. A positive response to CRT was dened as an LV end-systolic volume decreasing $15% after CRT.5 The duration at the last follow-up for echocardiography was 14 6 10 months. LV mechanical dyssynchrony was evaluated by the method of Perez using combined pulsed wave Doppler (PW) and tissue Doppler.6,7 The LV wall motion prole was assessed by tissue Doppler imaging (TDI) from the apical 4-chamber view. LV ejection was evaluated by PW at the level of the LV outow tract from the apical 5-chamber view. The following 2 time intervals were measured: (1) the onset of the Q wave to the end of the systolic wave at the basal lateral or septal segments with the greatest contraction delay assessed by TDI (TTDI) and (2) the onset of the Q wave to the end of LV ejection assessed by PW (TPW).6,7 Each measurement
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was taken from the average of 3 continuous cardiac cycles. The time difference (TTDI2PW) between TTDI and TPW . 50 milliseconds was dened as LV mechanical dyssynchrony6,7 Mitral inow was evaluated by PW at the tips of the mitral leaets in the apical 4-chamber view. The peak rapid lling (E wave) velocity, peak atrial lling (A wave) velocity, E wave deceleration time, and ratio of E/A were evaluated using PW. The rate of relaxation of the ventricle (E# wave), the rate of atrial contraction (A# wave), and the ratio E#/A#were evaluated using TDI at the septal side of the mitral annulus in the apical 4-chamber view. According to the pattern of the mitral ow recorded by PW and mitral annulus motion prole recorded using TDI, LV lling was classied into 4 patterns,8 including normal, relaxation abnormality, pseudonormalization, and restrictive lling. The severity of mitral regurgitation was classied into 3 grades: mild, moderate, and severe scales by color ow jet area as recommended by the guidelines of the American Society of Echocardiography.9 Mitral regurgitation $ moderate was dened as being signicant. The history of all patients, medications, and assessments of heart failure were obtained during regular outpatient visits and during hospitalizations. History and medications were also followed up by contacting patients on the telephone. The variables used in the analysis were as follows: (1) age; (2) gender; (3) QRS duration; (4) ischemic heart disease, dened as coronary artery stenosis $50%; (5) hypertension, dened as the condition of patients having received antihypertensive medication or having a blood pressure $140/90 mm Hg on repeated measurements10; (6) diabetes mellitus, dened as the condition of patients having a fasting plasma glucose $126 mg/dL, a postprandial glucose $200 mg/dL, or a random glucose $200 mg/dL11; (7) intrinsic or RV pacing-induced left bundle branch block (LBBB; pacemaker-dependent RV pacing for at least 6 months and upgrade of RV pacemaker or implantable cardioverter-debrillator to CRT); (8) TTDI2PW; (9) mitral valve ow pattern; (10) LV restrictive lling; (11) LV end-diastolic dimensions; (12) LV end-systolic dimensions; (13) LV hypertrophy, dened as an LV wall thickness .11 mm; (14) LV ejection fraction; (15) left atrial volume index; (16) mitral regurgitation degree; (17) signicant mitral regurgitation; (18) creatinine clearance, calculated by using the abbreviated Modication of Diet in Renal Disease equation12; (19) use of carvedilol; (20) use of metoprolol CR/XL; (21) use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers; (22) use of loop diuretics; (23) use of spironolactone; (24) use of both loop diuretics and spironolactone; (25)
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use of digoxin; (26) NYHA class; and (27) cardiac death during follow-up. The continuous variables were presented as mean 6 SD and were compared using 1-way analysis of variance. Categorical data were as assessed with the chi-square or the Fisher exact test if cell sizes were ,5. Variables that achieved a signicance level of P , 0.2 by Cox proportional univariate hazard model were reevaluated using a Cox proportional multivariate hazard model for evaluation of changes in hazard (risk) over time.13 We also included the variables in the Cox multivariate regression model, which were clearly related to the prognosis after CRT implantation. An SPSS version 18.0 software was used for all statistics. A P value of ,0.05 was considered statistically signicant.

RESULTS
The CRT implantation was successful in all 136 patients and did not give rise to any major complications. The LV capture threshold was 1.80 6 1.07 V. The mean LV pacing impedance was 994 6 349 ohms. Table 1 shows the baseline characteristics for the patients treated with carvedilol, with metoprolol CR/XL, and without beta blockers. No signicant differences were present between the 3 groups. The heart rate, QRS duration, creatinine clearance, and echocardiographic parameters before and after

CRT for patients treated with carvedilol, metoprolol CR/XL, and no beta blockers and levels of statistical signicance are listed in Table 2. During follow-up of 17 6 10 months after CRT, the QRS duration in patients treated with carvedilol signicantly decreased compared with baseline (P = 0.008). The LV ejection fraction in patients treated with Metoprolol CR/XL signicantly improved compared with baseline (P = ,0.0001). Left ventricular end-diastolic dimension (LVDd), left ventricular end-systolic volumes (LVVs), left ventricular ejection fraction (LVEF), and TTDI2PW in patients treated with metoprolol CR/XL signicantly improved compared with baseline. There was no signicant difference in heart rate among the 3 groups at baseline and after CRT. A decrease of $15% in LV end-systolic volume (CRT responders) was observed in 13 of 42 patients (31%) treated with carvedilol, in 44 of 80 patients (55%) treated with metoprolol CR/XL, and in 5 of 14 patients (36%) treated without beta blockers (P = 0.03) during follow-up of 14 6 10 months. There was a signicantly higher number of CRT responders treated with metoprolol CR/XL than with carvedilol (P = 0.02). Table 3 lists the results of Cox univariate regression for evaluation of 25 variables when the dependent variable was a positive response to CRT. The variables of NYHA class, ischemic heart disease, LV restrictive ow, mitral valve ow pattern, LV end-diastolic dimension, left atrial volume index, signicant mitral

Table 1. Baseline characteristics of patients treated with carvedilol, with metoprolol CR/XL, and with no beta blockers.* Variables Men Women Age (yrs) Heart rate NYHA class QRS duration (ms) RV pacing-induced LBBB LV ejection fraction (%) Echocardiographic follow-up (mos) Coronary artery disease Hypertension Diabetes Signicant mitral regurgitation Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers Loop diuretics Spironolactone Loop diuretics and spironolactone Digoxin Carvedilol (n = 42) 28 (67%) 14 (33%) 68 6 12 72 6 18 3.5 6 0.5 172 6 28 14 (33%) 22 6 7 12 6 10 23 (55%) 25 (60%) 15/42 19 (45%) 36 (86%) 33 (79%) 12 (29%) 7/(17%) 27 (64%) Metoprolol CR/XL (n = 80) 60 (75%) 20 (25%) 71 6 9 73 6 15 3.6 6 0.5 161 6 26 21 (26%) 20 6 7 15 6 10 55 (69%) 40 (50%) 33/80 25 (31%) 74 (93%) 64 33 28 56 (80%) (41%) (35%) (70%) No Beta Blockers (n = 14) 10 (71%) 4 (29%) 72 6 12 79 6 23 3.6 6 0.5 166 6 28 4 (29%) 20 6 7 14 6 12 10 (71%) 8 (57%) 6 (43%) 5 (36%) 13 (93%) 11 4 4 10 (79%) (29%) (29%) (71%)

*No signicant differences are present among the 3 groups.

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Table 2. Heart rate, QRS duration, creatinine clearance, and echocardiographic data at baseline and after CRT.* Carvedilol (n = 42) Baseline Heart rate QRS duration (ms) LVDd (mm) LVDs (mm) LVVs (ml) LVEF (%) LAVI (ml/m2) TTDI-PW (ms) CrCl (ml/1.73 m2) 72 172 65 53 183 22 63 67 56 6 6 6 6 6 6 6 6 6 18 28 11 12 84 7 28 55 22 CRT 74 154 63 54 179 26 58 49 57 6 6 6 6 6 6 6 6 6 12 31 12 13 90 11 24 33 28 P 0.54 0.008 0.51 0.57 0.83 0.06 0.41 0.08 0.85 Metoprolol CR/XL (n = 80) Baseline 73 161 64 54 188 20 59 66 58 6 6 6 6 6 6 6 6 6 15 26 9 10 77 7 21 49 20 CRT 73 156 61 51 160 28 56 44 58 6 6 6 6 6 6 6 6 6 13 28 10 12 78 13 20 31 26 P 0.79 0.23 0.04 0.070 0.02 ,0.0001 0.31 0.0006 0.82 No beta blockers (n = 14) Baseline 79 166 66 54 199 20 63 47 51 6 6 6 6 6 6 6 6 6 23 28 14 15 77 7 17 51 23 CRT 69 174 66 57 193 19 67 71 39 6 6 6 6 6 6 6 6 6 10 31 13 14 70 6 18 44 20 P 0.15 0.46 0.98 0.57 0.81 0.71 0.53 0.19 0.16

*CrCl, creatinine clearance; LAVI, left atrial volume index; LVDs, left ventricular end-systolic dimension.

regurgitation, spironolactone, loop diuretics plus spironolactone, digoxin, and TTDI2PW achieved a signicant level of P , 0.2. However, both carvedilol and metoprolol CR/XL were not related to CRT response. During the follow-up of 17 6 10 months after CRT, death occurred in 3 of 42 patients (7%) treated with

carvedilol, 14 of 80 patients (18%) treated with metoprolol CR/XL, and in 5 of 14 patients (36%) treated without beta blockers (P = 0.04). There was no signicant difference in mortality between patients treated with carvedilol or metoprolol CR/XL. Table 4 lists the results of Cox univariate regression for

Table 3. The results of Cox univariate regression for evaluation of 25 variables when the dependent variable was a positive response to cardiac resynchronization therapy.* Hazard ratio Male gender Age QRS duration NYHA class Ischemic heart disease Hypertension Diabetes mellitus RV pacing-induced LBBB TTDI-PW LV restrictive lling Mitral valve ow pattern LV end-diastolic dimension LV end-systolic dimension LV hypertrophy LV ejection fraction Left atrial volume index Mitral regurgitation $moderate Mitral regurgitation degree Creatinine clearance Metoprolol CR/XL Carvedilol ACEI/ARB Loop diuretics Spironolactone Loop diuretics + spironolactone Digoxin 0.72 0.99 1.00 0.67 0.45 1.12 0.85 0.99 1.01 0.67 0.71 0.98 0.99 1.22 1.02 0.99 0.61 0.90 1.00 1.49 1.01 1.20 0.76 0.62 0.62 0.63 95% CI for odds ratio P 0.23 0.33 0.71 0.13 0.002 0.65 0.54 0.98 ,0.0001 0.17 0.03 0.07 0.46 0.44 0.25 0.04 0.08 0.37 0.68 0.40 0.99 0.50 0.37 0.08 0.11 0.12 Lower 0.42 0.97 0.99 0.40 0.27 0.68 0.50 0.58 1.01 0.38 0.53 0.96 0.97 0.74 0.99 0.97 0.35 0.71 0.99 0.59 0.36 0.70 0.42 0.36 0.35 0.35 Upper 1.23 1.01 1.01 1.12 0.74 1.86 1.44 1.69 1.02 1.18 0.96 1.001 1.01 2.03 1.06 1.00 1.06 1.13 1.01 3.81 2.85 2.05 1.39 1.06 1.12 1.12

*ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers.

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evaluation of 25 variables when the dependent variable was cardiac mortality. The variables of diabetes mellitus, LV restrictive lling, mitral valve ow pattern, left atrial volume index, creatinine clearance, carvedilol, metoprolol CR/XL, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers achieved a signicant level of P , 0.2 by Cox univariate regression. After adjustment for age, male gender, and the variables with signicant differences by Cox univariate regression in patients treated with carvedilol and without beta blockers, the use of carvedilol [hazard ratio = 0.14; P = 0.03; 95% condence interval (CI) = 0.020.86] was found to be signicantly related to mortality (Table 5). Carvedilol was associated with a 7fold decrease in mortality. Creatinine clearance and use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers were also related to mortality. After adjustment for age, male gender, and the variables with signicant differences by Cox univariate regression in patients treated with metoprolol CR/XL

and without beta blockers, metoprolol CR/XL (hazard ratio = 0.19; P = 0.02; 95% CI = 0.040.80) was signicantly related to mortality (Table 6). Metoprolol CR/XL was associated with a 5-fold decrease in mortality. Male gender, mitral valve ow pattern, creatinine clearance, and use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers were also related to mortality.

DISCUSSION
Current guidelines emphasize the need for optimal medical therapy before use of CRT.1 At 10.4-month follow-up of 2289 patients with severe heart failure and an abnormal LV ejection fraction, compared with placebo, it was found that carvedilol signicantly reduced all-cause mortality by 35%.2 At the 1 year follow-up of 3991 patients with NYHA class II, III, or IV heart failure and an abnormal LV ejection fraction, the use of metoprolol CR/XL signicantly reduced all-

Table 4. The results of Cox univariate regression for evaluation of 25 variables when the dependent variable was death.* 95% CI for odds ratio Hazard ratio Male gender Age QRS duration NYHA class Ischemic heart disease Hypertension Diabetes mellitus RV pacing-induced LBBB TTDI-PW LV restrictive lling Mitral valve ow pattern LV end-diastolic dimension LV end-systolic dimension LV hypertrophy LV ejection fraction Left atrial volume index Mitral regurgitation $moderate Mitral regurgitation degree Creatinine clearance Metoprolol CR/XL Carvedilol ACEI/ARB Loop diuretics Spironolactone Loop diuretics + spironolactone Digoxin 2.13 1.01 1.00 1.14 1.33 1.49 1.86 0.87 0.99 3.45 2.49 0.99 0.99 0.80 0.98 1.02 1.25 1.19 0.96 0.43 0.22 0.51 0.82 1.14 1.10 0.67 P 0.23 0.58 0.97 0.76 0.58 0.37 0.16 0.78 0.46 0.006 0.006 0.79 0.76 0.62 0.59 0.006 0.62 0.41 0.001 0.11 0.04 0.13 0.69 0.76 0.83 0.38 Lower 0.62 0.97 0.99 0.48 0.49 0.62 0.78 0.34 0.99 1.43 1.30 0.96 0.96 0.34 0.92 1.01 0.53 0.79 0.94 0.16 0.05 0.22 0.30 0.49 0.45 0.28 Upper 7.27 1.06 1.02 2.72 3.64 3.55 4.42 2.24 1.01 8.33 4.76 1.04 1.03 1.91 1.05 1.04 2.96 1.80 0.98 1.21 0.94 1.21 2.23 2.67 2.72 1.63

ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers.

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6 Table 5. The results of Cox multivariate regression in patients treated with carvedilol and without beta blockers for the evaluation of the variables with signicant differences by Cox univariate regression when the dependent variable was death.* 95% CI for odds ratio P 0.09 0.94 0.11 0.24 0.40 0.69 0.02 0.10 0.03 Lower 0.75 0.92 0.67 0.44 0.49 0.98 0.88 0.02 0.02 Upper 68.77 1.08 51.58 24.57 5.88 1.04 0.99 1.37 0.86

Shen et al

Hazard ratio Male gender Age Diabetes mellitus LV restrictive lling Mitral valve ow pattern Left atrial volume index Creatinine clearance ACEI/ARB Carvedilol 7.17 1.00 5.89 3.30 1.70 1.01 0.93 0.18 0.14

*ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers.

cause mortality by 34%.3 Carvedilol and metoprolol CR/XL are the 2 beta blockers approved by the United States Food and Drug administration for the treatment of heart failure. To the best of our knowledge, a comparison of the effects of using carvedilol versus using metoprolol CR/XL on mortality and on CRT response in patients with heart failure treated with CRT has not been previously reported. Beta blockers were not used in 10% of the patients in our study because of

Table 6. The results of Cox multivariate regression in patients treated with metoprolol CR/XL and without beta blockers for the evaluation of the variables with significant differences by Cox univariate regression when the dependent variable was death.* 95% CI for odds ratio P 0.04 0.99 0.14 0.10 0.05 0.06 0.02 0.004 0.02 Lower Upper 1.13 0.95 0.75 0.005 0.97 1.00 0.94 0.06 0.04 47.34 1.05 7.03 1.53 54.89 1.06 0.99 0.58 0.80

Hazard ratio Male gender Age Diabetes mellitus LV restrictive lling Mitral valve ow pattern Left atrial volume index Creatinine clearance ACEI/ARB Metoprolol CR/XL 7.31 1.00 2.30 0.09 7.31 1.03 0.97 0.18 0.19

contraindications to use of beta blockers. Cox multivariate regression analysis showed that compared with no use of beta blockers, carvedilol signicantly reduced all-cause mortality 7 times, and metoprolol CR/XL signicantly reduced mortality 5 times. There was no signicant difference in all-cause mortality between carvedilol and metoprolol CR/XL. Both carvedilol and metoprolol CR/XL were not related to a positive CRT response by Cox univariate regression analysis. One basis for comparing beta blockers agents is the effect on heart rate. Heart rate is a major determinant of myocardial oxygen consumption and cardiac workload. An elevated heart rate is frequently seen in patients with congestive heart failure and is in large part the result of increased sympathetic activity and decreased parasympathetic activity. In this study, the heart rates before and after undergoing CRT were not signicantly different between patients treated with carvedilol and those treated with metoprolol CR/XL. The detection rate of patients responding to CRT was lower in those with heart failure and a wide QRS duration in both the study of Perez6,7 (39%) and our study (43%) compared with in other studies (60% 75%).14 This is consistent with previous studies showing that CRT is less benecial among heart failure patients with ischemic heart disease than in patients with nonischemic heart disease as is also the case in our study.1517 A limitation of this study is that it is not a prospective, randomized study with a larger study population receiving CRT comparing the effect of carvedilol versus metoprolol CR/XL on all-cause mortality and on response to CRT. Such a study needs to be performed. However, the data from this study support the use of either carvedilol or metoprolol CR/XL in patients with heart failure treated with CRT to reduce all-cause mortality. Another limitation of this study is that although multivariate analysis showed that both carvedilol and metoprolol CR/XL signicantly reduced mortality in patients with heart failure treated with CRT compared with patients with heart failure unable to tolerate beta blockers and treated with CRT, the very high mortality in patients who could not tolerate beta blockers may partly be due to their being sicker.

REFERENCES
1. Jessup M, Abraham WT, Casey DE, et al. 2009 focused update: ACCF/AHA guidelines for the diagnosis and management of heart failure in adults. A Report of the American College of Cardiology Foundation/American www.americantherapeutics.com

ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers.

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Beta Blockers in CRT Heart Association Task force on Practice Guidelines. J Am Coll Cardiol. 2009;53:13431382. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:16511658. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERITHF). Lancet. 1999;353:20012007. Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantication: a report from the American Society of Echocardiographys Guidelines and Standards Committee and the Chamber Quantication Writing Group. Developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18:14401463. Pitzalis MV, Iacoviello M, Romito R, et al. Cardiac resynchronization therapy tailored by echocardiographic evaluation of ventricular asynchrony. J Am Coll Cardiol. 2002;40:16151622. Perez de Isla L, Ortiz Ocialdegui P, Florit J, et al. RAVE usefulness of clinical, electrocardiographic, and echocardiographic parameters to detect cardiac asynchrony in patients with left ventricular dysfunction secondary to ischemic or nonischemic heart disease. J Am Soc Echocardiogr. 2006;19:13381344. Perez de Isla L, Florit J, Garcia-Fernandez MA, et al. Prevalence of echocardiographically detected ventricular asynchrony in patients with left ventricular systolic dysfunction. J Am Soc Echocardiogr. 2005;18:850859. Sohn D-W, Chai I-H, Lee D-J, et al. Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol. 1997;30:474480. Zoghbi WA, Enriquez-Sarano M, Foster E, et al. Recommendations for evaluation of the severity of native valvular

7 regurgitation with two-dimensional and Doppler echocardiography. Am J Soc Echocardiogr. 2003;16:777802. Mancia G, De Backer G, Dominiczak A, et al. 2007 guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertension. 2007;25:11051187. American Diabetes Association. Clinical practice recommendations 1999 (position statement). Diabetes Care. 1999; 22(Suppl 1):S1S114. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular ltration rate from serum creatinine: a new prediction equation. Modication of Diet in Renal Disease Study Group. Ann Intern Med. 1999; 130:461470. Antman EM, Cohen M, Bernink PJLM, et al. The TIMI risk score for unstable angina/nonST elevation MI: a method for prognostication and therapeutic decision making. JAMA. 2000;284:835842. Yu CM, Fung JW, Zhang Q, et al. Tissue Doppler imaging is superior to strain rate imaging and postsystolic shortening on the prediction of reverse remodeling in both ischemic and nonischemic heart failure after cardiac resynchronization therapy. Circulation. 2004;110: 6673. Bleeker GB, Kaandorp TAM, Lamb HJ, et al. Effect of posterolateral scar tissue on clinical and echocardiographic improvement after cardiac resynchronization therapy. Circulation. 2006;113:969976. Gasparini M, Mantica M, Galimberti P, et al. Is the outcome of cardiac resynchronization therapy related to the underlying etiology? PACE. 2003;26:175180. Shen X, Aronow WS, Nair CK, et al. Are the extent, location and score of segmental wall motion abnormalities related to cardiac resynchronization therapy response? Echocardiography. 2009;26:11361145.

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