Carvedilol or Sustained-Release Metoprolol for Congestive Heart Failure: A Comparative Effectiveness Analysis

Journal of Cardiac Failure Vol. 18 No. 12 2012

Carvedilol or Sustained-Release Metoprolol for Congestive Heart Failure: A Comparative Effectiveness Analysis SUPRIYA SHORE, MD,1 VIKAS AGGARWAL, MD, MPH,2 AND RONALD ZOLTY, MD, PhD3 The Bronx, New York; and Aurora, Colorado

ABSTRACT Background: Relative effectiveness of carvedilol and metoprolol succinate has never been compared in patients with heart failure (HF). Methods and Results: From January 1998 to December 2008, 3,716 consecutive patients with ejection fraction (EF) #40%, initiated and maintained on carvedilol or metoprolol succinate, were enrolled and followed until June 2010. The primary end point was all-cause mortality, and the secondary end points were readmissions from HF and follow up EFs at 1, 3, and 5 years. HF etiology (ischemic or nonischemic) was a significant effect modifier, and separate analysis was performed for these subcohorts. Compared with those on carvedilol, patients on metoprolol succinate were less likely to experience mortality in the ischemic HF cohort (adjusted hazard ratio [aHR] 0.54, 95% confidence interval [CI] 0.43e0.66) but were more likely to die in the nonischemic HF cohort (aHR 1.18, 95% CI 1.10e1.28). Follow-up EF was similar by type of beta-blocker used in both ischemic and nonischemic HF cohorts. Furthermore, no significant difference was noted in the incidence of HF hospitalizations by beta-blocker type used in both ischemic and nonischemic HF cohorts. Conclusions: Metoprolol succinate was associated with an improved survival in patients with ischemic HF, and carvedilol was associated with an improved survival in patients with nonischemic HF. (J Cardiac Fail 2012;18:919e924) Key Words: Carvedilol, metoprolol succinate, sustained-release metoprolol, heart failure, comparative effectiveness.

Beta-blocker therapy continues to be a cornerstone in reducing cardiovascular events and mortality in patients with heart failure (HF) and systolic dysfunction.1 Metoprolol and carvedilol are two of the most commonly used beta blockers in patients with HF.1 Metoprolol is a selective beta-1 blocker, devoid of intrinsic sympathomimetic activity whereas, carvedilol blocks beta-1, beta-2, and alpha-1 adrenergic receptors.2,3 Metoprolol is available as a conventional twice-daily formulation (metoprolol tartarate) and

a controlled-release/extended-release formulation (metoprolol succinate) that provides constant plasma concentrations and beta-1 blockade and has the convenience of once-daily administration. Randomized clinical trials have compared carvedilol, metoprolol succinate, and bisoprolol to either metoprolol tartarate or placebo, but despite being widely used, carvedilol and metoprolol succinate have never been compared head to head in patients with HF.4e9 In the present study, we sought to determine the comparative effectiveness of metoprolol succinate versus carvedilol using a large cohort of HF patients at an urban university medical centerebased HF service.

From the 1Department of Medicine, Jacobi Medical Center, Albert Einstein College of Medicine, The Bronx, New York; 2Division of Cardiology, Department of Medicine, University of Colorado (Anschutz Medical Campus), Aurora, Colorado and 3Division of Cardiology, Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, The Bronx, New York. Manuscript received November 9, 2011; revised manuscript received October 15, 2012; revised manuscript accepted October 24, 2012. Reprint requests: Ronald Zolty, MD, PhD, Director, Heart Failure Service, Montefiore Medical Center (Weiler Division), Albert Einstein College of Medicine, 1300 Morris Park Ave, Room G46B, The Bronx, NY 10461. Tel: 718-430-2645; Fax: 718-430-8989. E-mail: [email protected] See page 923 for disclosure information. 1071-9164/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cardfail.2012.10.016

Methods Study Population All consecutive patients who were prescribed carvedilol or metoprolol succinate for new-onset congestive HF with an ejection fraction (EF) of !40% were enrolled in the present study over a 10 year period from January 1, 1998, to January 1, 2008, at Montefiore Medical Center. Patients had to be maintained on either carvedilol or metoprolol succinate only and receiving optimal treatment (defined as any combination of diuretics and an angiotensin-converting enzyme [ACE] inhibitor) for $4 weeks

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920 Journal of Cardiac Failure Vol. 18 No. 12 December 2012 before study enrollment. If an ACE inhibitor was not tolerated, hydralazine, long-acting nitrates, or an angiotensin receptor blocker could be used. All patients were enrolled during an outpatient visit and had to be New York Heart Association (NYHA) functional class 3 or worse. Patients with a myocardial infarction, coronary artery bypass grafting, or valvular surgery within 12 weeks or HF from a primary valvular disorder were excluded. Approval was obtained from the Institutional Review Board before initiation of the study. Data Collection and Outcomes All charts for inpatient hospital stay and outpatient visits were reviewed. Demographic, clinical, and laboratory data were collected via intensive chart review, and echocardiographic images were digitally acquired and independently analyzed by a blinded reviewer. Heart rate assessment was made during regular ambulatory follow-up visits and not during inpatient admissions for HF exacerbations. The EF was estimated with the use of the Teichholz method.10 Ischemic HF was adjudicated by experienced cardiologists based on evidence of significant coronary artery disease on coronary angiogram. Pulmonary artery systolic pressure was estimated with the use of standard methods on transthoracic echocardiography (peak systolic velocity of tricuspid regurgitation jet and inferior vena cava assessment). Glomerular filtration rate was estimated with the use of the Modification of Diet in Renal Disease formula. Low-dose beta-blocker therapy was defined as #100 mg/d metoprolol succinate or #12.5 mg/d carvedilol. All higher doses were classified as high-dose beta-blocker therapy. We used the beta-blocker dose most often administered to the patient for the purpose of this differentiation. The primary outcome of this study was all-cause mortality, which was ascertained with the use of the national Social Security death index. We used number of inpatient hospital admissions per 1,000 patients for HF and follow-up EFs at 1 year, 3 year, and 5 years as our secondary outcomes, which were also ascertained via chart review. Statistical Analyses Differences between the 2 groups (carvedilol and metoprolol succinate) regarding demographics, clinical characteristics, use of other HF medications, and other potentially confounding factors were examined with the use of unpaired Student t test for normally distributed continuous variables, Wilcoxon rank sum test for nonnormally distributed continuous variables, or chi-square test for categoric variables. We also tested for effect modification and interactions by race, sex, beta-blocker dose, incidence of diabetes mellitus, and etiology of HF (ischemic or nonischemic). Evidence for effect modification was observed by HF etiology and betablocker use. Therefore, all analysis was performed separately for ischemic HF and nonischemic HF cohorts. For the purpose of estimating hazard of experiencing all-cause mortality, Cox proportional hazards regression modeling was used. The model was adjusted for age, sex, race, NYHA functional class, history of hypertension, diabetes status, chronic obstructive lung disease, pulmonary artery systolic pressure, use of other HF medications, and glomerular filtration rate (GFR). The aforementioned Cox proportional hazards regression analyses were also conducted for the following subgroups in both ischemic and nonischemic HF cohorts: 1. Patients with diabetes mellitus. 2. Patients with obstructive lung disease.

3. Patients on low-dose beta-blocker therapy. 4. Patients on high-dose beta-blocker therapy. For the secondary end points, baseline and follow-up EFs at 1 year were first compared with the use of standard t test for both ischemic and nonischemic HF cohorts. Furthermore, an analysis of covariance approach was used to compare change in EF from baseline to 1 year with metoprolol succinate and carvedilol adjusted for baseline EF and etiology of HF (ischemic vs nonischemic HF). Because individual patient-level data for hospitalizations were unavailable, only unadjusted analysis comparing readmissions per patient-years was carried out with the use of standard t test. All statistical tests were 2 sided, and a P value of .05 was considered to be significant. All analyses were performed with the use of Stata statistical software (College Station, Texas).

Results Study Characteristics

We initially screened 4,095 patients for the study who met our initial inclusion and exclusion criteria, but only 3,716 patients were compliant with their beta-blocker at 4 weeks, 52% (1,932/3,716) of them with ischemic HF and 48% (1,784/3,716) with nonischemic HF. These patients were subsequently included in the study. Mean age for the entire cohort was 61 years, 53% (1,980/3,716) were female, 21% (789/3,716) were white, and !1% (36/ 3,716) patients received a mechanical support device or a transplant. As mentioned earlier, etiology of HF (ischemic vs nonischemic) was noted to be a key effect modifier in this analysis and separate analyses were therefore performed to control for it. Otherwise, there was no significant interaction between sex, race, or any other clinical characteristic and beta-blocker use for either mortality or number of hospitalizations (P O .70 for all interactions). Mean follow up duration was 4.0 years for the ischemic HF group and 3.5 years for the nonischemic HF group. Table 1 shows baseline comparisons in key demographic, clinical, and laboratory variables by type of beta-blocker used (carvedilol or metoprolol succinate). For the ischemic HF cohort, patients on metoprolol succinate had a nonsignificant marginally higher incidence of diabetes mellitus, hypertension, and chronic kidney disease (P ! .20), but the incidences of all other characteristics were similar. Interestingly, however, the incidences of hypertension and chronic kidney disease were nonsignificantly higher in the carvedilol group for nonischemic HF (P ! .20), but the incidence of diabetes mellitus was similar (P 5 .36). Baseline EF was similar by beta-blocker use in both ischemic HF and nonischemic HF cohorts. All other baseline comparisons were also very similar in both subcohorts. Primary End Point: All-Cause Mortality

After adjusting for significant risk factors and medications (as mentioned earlier) that have been shown to alter mortality in the patients with HF, patients with ischemic HF on metoprolol succinate had a significantly lower

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Table 1. Baseline Characteristics of the Study Population by Beta-Blocker Use for Ischemic and Nonischemic Heart Failure (HF) Cohorts Ischemic HF (n 5 1,932) Characteristic Age, years mean (SD) Female sex, % Race, % White Black Hispanic Other NYHA IV, % Chronic obstructive lung disease, % Diabetes mellitus, % Hypertension, % Hyperlipidemia, % Current smoker, % Baseline EF, mean (SD) Baseline HR, median (IQR) Pulmonary hypertension,* % Aspirin use, % Statin use, % Heart failure medications, % ACE inhibitors ARBs Diuretics Hydralazine Nitrates Spironolactone Digoxin GFR, mean (SD)

Nonischemic HF (n 5 1,784)

Carvedilol (n 5 946)

Metoprolol Succinate (n 5 986)

Carvedilol (n 5 810)

Metoprolol Succinate (n 5 974)

63.3 (14.8) 53.4

62.8 (14.6) 52.3

59.2 (12.3) 54.3

58.1 (13.3) 53.2

24.1 35.3 39.6 1.0 24.2 42.6 55.6 89.4 70.6 32.4 32.8 (5.9) 87 (21) 26.3 94.2 84.1

22.3 37.7 38.7 1.3 23.3 40.6 57.3 87.0 71.3 32.6 32.5 (6.3) 88 (20) 25.5 93.9 84.5

19.0 41.1 34.4

19.3 42.4 33.2

29.1 39.1 35.2 40.1 33.2 28.4 30.3 (8.4) 92 (18) 35.3 79.3 82.1

29.9 38.3 36.1 42.2 31.2 27.9 30.7 (8.6) 94 (19) 34.4 80.2 82.3

66.5 22.8 71.0 16.6 24.7 26.2 31.1 65.3 (17.6)

68.2 22.5 70.8 17.2 24.8 27.0 32.0 64.4 (16.4)

60.2 16.3 80.3 26.6 29.8 44.4 33.3 64.5 (16.8)

58.2 17.8 82.3 27.7 31.1 43.2 32.2 63.3 (17.1)

ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; EF, ejection fraction, %; GFR, glomerular filtration rate in mL/min; HR, heart rate, beats/min; IQR, interquartile range; NYHA, New York Heart Association functional class. All P values were O 0.10. *Pulmonary Hypertension was defined as pulmonary artery systolic pressure $40 mmHg.

hazard of experiencing mortality (adjusted hazard ratio [aHR] 0.54, 95% confidence interval [CI] 0.43e0.66) compared with patients with ischemic HF on carvedilol. Conversely, after adjustment for all available confounders, patients in the nonischemic HF group had a significantly

lower hazard of experiencing mortality on carvedilol (aHR 0.85, 95% CI 0.78e0.91) compared with patients with nonischemic HF on metoprolol succinate. Similar results were also noted on unadjusted survival analysis (Figs. 1 and 2). Furthermore, as presented in Tables 2 and 3, similar results were seen on restricting our analysis to: 1) patients with diabetes mellitus; 2) patients with obstructive lung disease; 3) patients on high-dose beta-blockers; and 4) patients on low-dose beta-blockers. Secondary End Points

Ejection Fraction. Ischemic HF Cohort. Mean (SD) baseline EFs were similar by beta-blocker use: 32.5% (6.3%) for the metoprolol succinate group and 32.8% (5.9%) for the carvedilol group; P 5 .28. Furthermore, no significant difference in EF was noted at 1-year follow-up: 35.5% (4.2%) for the metoprolol succinate group (n 5 928) and 35.3% (4.8%) for the carvedilol group (n 5 907); P 5 .34. Fig. 1. Unadjusted survival curves for patients with ischemic heart failure. The x axis denotes follow-up duration in years, and the y axis denotes proportion of patients experiencing mortality. The dashed line represents patients treated with carvedilol, and the solid line represents patients treated with metoprolol succinate.

Nonischemic HF Cohort. Mean (SD) baseline EFs were similar by beta-blocker use: 30.7% (8.6%) for the metoprolol succinate group and 30.3% (8.4%) for the carvedilol group; P 5 .32. Furthermore, no significant difference in

922 Journal of Cardiac Failure Vol. 18 No. 12 December 2012 carvedilol, whereas those with nonischemic HF had better survival on carvedilol. To the best of our knowledge, this is the first study comparing metoprolol succinate and carvedilol in patients with HF. Similar results were also observed on subgroup analysis restricted to patients with diabetes mellitus, obstructive lung disease, and low- or high dose beta-blocker in both ischemic and nonischemic HF cohorts. The COMET (Carvedilol or Metoprolol European Trial)4 showed better outcomes with carvedilol compared with metoprolol tartarate in patients with ischemic as well as nonischemic HF. Furthermore, metoprolol tartarate and succinate may be similar in their molecular mechanisms of action, but there are several reasons that may have led to our results being different from those observed in the COMET. Metoprolol succinate has a longer duration of action compared with metoprolol tartarate (24 h vs 8e12 h), which allows for a once-daily administration and stable plasma concentrations with minimal fluctuations over a 24-hour dosing period.11 Thus, metoprolol tartarate compared with metoprolol succinate has greater fluctuations in plasma levels, with higher peaks and lower troughs.11 The higher peak concentrations lead to surges of maximal beta-receptor blockade and loss of selectivity, and the lower troughs lead to loss of beta-1 blockade and potential rebound.12 The more sustained beta-blockade offered by metoprolol succinate over tartarate leads to a more sustained beta-1 selective blockade over a 24-hour period.11 Similar logic may also apply to carvedilol, and it is very likely that patients are achieving a steadier beta-blocker effect with metoprolol succinate than carvedilol. Furthermore, excess early mortality and morbidity in the MOXCON (Sustained-Release Moxonidine for Congestive Heart Failure) study raised concerns regarding the efficacy of generalized sympathetic inhibition in HF; a majority of participants enrolled in that trial had ischemic HF.13 Additionally, the majority of subjects enrolled in the COMET were white, whereas we had a more racially diverse study population and our results might driven in part by differential effects of beta-blockers in different race and sex subgroups.14 Other possible explanations for different results by the type of beta-blocker prescribed (metoprolol succinate or carvedilol) may stem from differences in underlying pathophysiology of ischemic and nonischemic HF. Beta-1

Fig. 2. Unadjusted survival curves for patients with nonischemic HF. The x axis denotes follow up duration in years, and the y axis denotes proportion of patients experiencing mortality. The dashed line represents patients treated with carvedilol, and the solid line represents patients treated with metoprolol succinate.

EF was noted at 1-year follow-up: 35.2% (4.8%) for the metoprolol succinate group (n 5 937) and 35.4% (4.7%) for the carvedilol group (n 5 778); P 5 .39. Additionally, analysis of covariance also did not show any difference in change in EF from baseline by betablocker use even after controlling for baseline EF and etiology for HF (ischemic vs nonischemic): F 5 0.30; P 5 .59. Repeat Hospitalizations. Among those with ischemic cardiomyopathy, patients on carvedilol had a mean (SD) of 124 (83) hospitalizations per 100 patient-years compared with 121 (88) for those on metoprolol succinate in the first year after enrollment. This difference was not statistically significant (P 5 .34). Among those with nonischemic cardiomyopathy, patients on carvedilol had a mean (SD) of 116 (81) hospitalizations per 100 patient-years compared with 114 (83) for those on metoprolol succinate in the first year after enrollment. This difference also was not statistically significant (P 5 .38). Discussion The results of this study suggest that patients with ischemic HF do better on metoprolol succinate compared with

Table 2. Hazard of Experiencing All-Cause Mortality on Metoprolol Succinate Compared With Carvedilol (Reference) in Patients With Ischemic Heart Failure (HF) During the 10-Year Study Period No. of Deaths All patients (n 5 1,932) Only obstructive lung disease (n 5 803) Low-dose beta-blocker therapy (n 5 1,062) High-dose beta-blocker therapy (n 5 870) Only diabetes mellitus (n 5 1091)

541 241 287 254 327

Unadjusted HR (95% CI) 0.69 0.67 0.76 0.68 0.77

(0.53e0.80)** (0.40e0.86)** (0.49e0.93)* (0.40e0.87)* (0.49e0.98)*

Adjusted HR (95% CI) 0.54 0.50 0.55 0.52 0.66

(0.43e0.66)** (0.23e0.76)** (0.35e0.73)** (0.30e0.78)** (0.39e0.90)*

Follow-Up, Months, Mean (SD) 48 47 46 49 48

(26) (35) (34) (33) (34)

CI, confidence interval; HR, hazard ratio. HRs were adjusted for age, sex, race, New York Heart Association functional class, history of hypertension, diabetes status, chronic obstructive lung disease, pulmonary artery systolic pressure, use of other HF medications, and glomerular filtration rate (GFR). *P ! .05; **P ! .001.

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Table 3. Hazard of Experiencing All-Cause Mortality on Metoprolol Succinate Compared With Carvedilol (Reference) in Patients With Nonischemic Heart Failure (HF) During the 10-Year Study Period No. of Deaths, n All patients (n 5 1,784) Only obstructive lung disease (n 5 690) Low-dose beta-blocker therapy (n 5 963) High-dose beta-blocker therapy (n 5 821) Only diabetes mellitus (n 5 637)

393 165 217 176 160

Unadjusted HR (95% CI) 1.31 1.21 1.29 1.29 1.31

(1.21e1.40)** (1.04e1.38)* (1.09e1.45)* (1.11e1.46)* (1.13e1.57)**

Adjusted HR (95% CI) 1.18 1.12 1.20 1.17 1.20

(1.10e1.28)* (0.94e1.29) (1.04e1.35)* (1.01e1.35)* (1.02e1.38)*

Follow-Up, Months, Mean (SD) 45 46 45 46 45

(27) (36) (37) (35) (32)

Abbreviations as in Table 2. HRs were adjusted for age, gender, race, New York Heart Association functional class, history of hypertension, diabetes status, chronic obstructive lung disease, pulmonary artery systolic pressure, use of other HF medications, and GFR. *P ! .05, **P ! .001.

receptor density is higher (owing to less beta-1 receptor down-regulation) and greater beta-1/beta-2 receptor uncoupling is seen in patients with ischemic HF compared with nonischemic HF.15 Therefore, a beta-1eselective agent such as metoprolol may possess greater efficacy in patients with ischemic HF. Furthermore, greater sympathetic denervation of cardiac myocytes from prior myocardial infarctions in those with ischemic HF16 may lead to lower levels of norepinephrine in such patients compared with those with nonischemic HF.17e20 Thus, a nonselective beta-blocker such as carvedilol, which reduces cardiac norepinephrine levels more effectively, may be more efficacious in patients with nonischemic HF.15,17e21 Important limitations to the present study include its observational single-center design, lack of individual patientlevel repeated hospitalization data, and the presence of residual confounding despite observing remarkably similar baseline patient characteristics in both subgroups and adjustment for all available key characteristics. However, from a practical perspective, medication compliance, patient follow-up, and dosage up-titration efficacy in a clinical trial will never be similar to the real-world setting, and an observational study on a large cohort of patients such as this one enabled us to compare these 2 very commonly used drugs in a ‘‘real-world scenario.’’ An advantage of the present study is the large population in the two study cohorts with very similar baseline characteristics. In conclusion, we think that these results may benefit physicians who are frequently confronted with a dilemma to switch metoprolol to carvedilol in patients who are being treated with such an agent for hypertension or ischemic heart disease when they develop HF. Acknowledgments The authors thank the heart failure and echocardiography laboratory staff at Montefiore Medical Center for their important contributions with data collection and patient follow-ups. Disclosures None.

References 1. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al. 2009 focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009;119:e391e479. 2. Yoshikawa T, Port JD, Asano K, Chidiak P, Bouvier M, Dutcher D, et al. Cardiac adrenergic receptor effects of carvedilol. Eur Heart J 1996;17(Suppl B):8e16. 3. Papadopoulos DP, Papademetriou V. Metoprolol succinate combination in the treatment of hypertension. Angiology 2009;60:608e13. 4. Poole-Wilson PA, Swedberg K, Cleland JG, di Lenarda A, Hanrath P, Komajda M, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003;362:7e13. 5. Bonet S, Agusti A, Arnau JM, Vidal X, Diogene E, Galve E, Laporte JR. Beta-adrenergic blocking agents in heart failure: benefits of vasodilating and nonvasodilating agents according to patients’ characteristics: a meta-analysis of clinical trials. Arch Intern Med 2000; 160:621e7. 6. Metra M, Giubbini R, Nodari S, Boldi E, Modena MG, Dei Cas L. Differential effects of beta-blockers in patients with heart failure: a prospective, randomized, double-blind comparison of the long-term effects of metoprolol versus carvedilol. Circulation 2000;102:546e51. 7. Packer M, Antonopoulos GV, Berlin JA, Chittams J, Konstam MA, Udelson JE. Comparative effects of carvedilol and metoprolol on left ventricular ejection fraction in heart failure: results of a meta-analysis. Am Heart J 2001;141:899e907. 8. Gilbert EM, Abraham WT, Olsen S, Hattler B, White M, Mealy P, et al. Comparative hemodynamic, left ventricular functional, and antiadrenergic effects of chronic treatment with metoprolol versus carvedilol in the failing heart. Circulation 1996;94:2817e25. 9. Sanderson JE, Chan SK, Yip G, Yeung LY, Chan KW, Raymond K, Woo KS. Beta-blockade in heart failure: a comparison of carvedilol with metoprolol. J Am Coll Cardiol 1999;34:1522e8. 10. Cohen M, Monsen C, Francis X, Sherman W, Ambrose JA, Teichholz LE, Fuster V. Comparison of single plane videodensitometrye based right ventricular ejection fraction in right and left anterior oblique views to biplane geometryebased right ventricular ejection fraction. J Am Coll Cardiol 1987;10:150e5. 11. Sandberg A, Blomqvist I, Jonsson UE, Lundborg P. Pharmacokinetic and pharmacodynamic properties of a new controlled-release formulation of metoprolol: a comparison with conventional tablets. Eur J Clin Pharmacol 1988;33(Suppl):S9e14. 12. Wikstrand J. Achieving optimal beta1-blockade with metoprolol CR/Zok. Basic Res Cardiol 2000;95(Suppl 1):I46e51. 13. Cohn JN, Pfeffer MA, Rouleau J, Sharpe N, Swedberg K, Straub M, Wiltse C, Wright TJ. Adverse mortality effect of central sympathetic

924 Journal of Cardiac Failure Vol. 18 No. 12 December 2012

14.

15.

16.

17.

inhibition with sustained-release moxonidine in patients with heart failure (MOXCON). Eur J Heart Fail 2003;5:659e67. Petersen M, Andersen JT, Hjelvang BR, Broedbaek K, Afzal S, Nyegaard M, et al. Association of beta-adrenergic receptor polymorphisms and mortality in carvedilol-treated chronic heart-failure patients. Br J Clin Pharmacol 2011;71:556e65. Bristow MR, Anderson FL, Port JD, Skerl L, Hershberger RE, Larrabee P, et al. Differences in beta-adrenergic neuroeffector mechanisms in ischemic versus idiopathic dilated cardiomyopathy. Circulation 1991;84:1024e39. Barber MJ, Mueller TM, Henry DP, Felten SY, Zipes DP. Transmural myocardial infarction in the dog produces sympathectomy in noninfarcted myocardium. Circulation 1983;67:787e96. Fishman PH, Mallorga P, Tallman JF. Catecholamine-induced desensitization of adenylate cyclase in rat glioma C6 cells. Evidence for a specific uncoupling of beta-adrenergic receptors from a functional regulatory component of adenylate cyclase. Mol Pharmacol 1981;20:310e8.

18. Bristow MR, Ginsburg R, Umans V, Fowler M, Minobe W, Rasmussen R, et al. Beta 1- and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1receptor down-regulation in heart failure. Circ Res 1986;59:297e309. 19. Brodde OE, Schuler S, Kretsch R, Brinkmann M, Borst HG, Hetzer R, et al. Regional distribution of beta-adrenoceptors in the human heart: coexistence of functional beta 1- and beta 2-adrenoceptors in both atria and ventricles in severe congestive cardiomyopathy. J Cardiovasc Pharmacol 1986;8:1235e42. 20. Bristow MR, Kantrowitz NE, Ginsburg R, Fowler MB. Beta-adrenergic function in heart muscle disease and heart failure. J Mol Cell Cardiol 1985;17(Suppl 2):41e52. 21. Woodley SL, Gilbert EM, Anderson JL, O’Connell JB, Deitchman D, Yanowitz FG, et al. Beta-blockade with bucindolol in heart failure caused by ischemic versus idiopathic dilated cardiomyopathy. Circulation 1991;84:2426e41.