Circ J 2003; 67: 826–829

Effect of Beta-Blocker Therapy in Elderly Patients With Dilated Cardiomyopathy

Yuji Hara, MD; Mareomi Hamada, MD; Yuji Shigematsu, MD; Tomoaki Ohtsuka, MD; Akiyoshi Ogimoto, MD; Jun Suzuki, MD; Jitsuo Higaki, MD

The aim of this study was to evaluate whetherβ-blocker therapy can be safely administered to and improve cardiac function of elderly patients with dilated cardiomyopathy (DCM). Echocardiography and measurement of the concentrations of natriuretic peptides were carried out in 67 patients with DCM before and after 6 months of β-blocker therapy: 20 patients ≥65 years of age (older group); 47 <65 years of age (younger group). In all patients,β-blocker was safely administered and well tolerated. There was no significant difference in the dose of β-blocker between 2 groups. A reduction in the left ventricular dimensions and an associated increase in ejection fraction occurred in both treatment groups. The β-blocker treatment resulted in a significant decrease in the concentrations of natriuretic peptides in both groups. In conclusion,β-blocker therapy is well-tolerated and has similar effects on cardiac function in older and younger patients with DCM. (Circ J 2003; 67: 826–829) Key Words: Dilated cardiomyopathy; Beta-blockers; Elderly patients; Natriuretic peptides

n 1975, Waagstein et al reported for the first time that tution approved the study protocol and all patients provided patients with severe heart failure showed clinical informed consent before participating in the study. I improvement after the administration of aβ-blocker,1 and since then, the beneficial effect ofβ-blocker therapy in Study Protocol patients with chronic congestive heart failure (CHF) has Following their admission to hospital, all patients with been confirmed in many studies.2–7 However, little is known DCM were given baseline biochemical and echocardiogra- about the effect and safety ofβ-blocker therapy in elderly phic examinations. A β-blocker was then added to the patients with CHF, so we examined whether elderly pa- patient’s other concomitant medications for a period of 6 tients with dilated cardiomyopathy (DCM) can be safely months: 29 patients received metoprolol, 19 received treated and whether these drugs can improve their cardiac bevantolol and 19 received carvedilol. The initial dosage of function. metoprolol and bevantolol was 2.5 or 5mg/day and the initial dosage of carvedilol was 1.25 or 2.5mg/day. The dose was increased every 5 to 7 days. Maintenance doses Methods were determined on the basis of heart rate at rest ranging Subjects from 50 to 70beats/min. Dose titration was deferred or Patients were considered eligible for the study if they had stepped back if symptoms worsened or systolic blood pres- symptomatic heart failure and left ventricular fractional sure decreased to less than 90mmHg or heart rate at rest shortening of less than 25%. In addition, study patients had decreased to less than 50 beats/min. Mean maintenance to be clinically stable on the standard therapy of digoxin, doses were 38±16 mg (range 10–75 mg) for metoprolol, diuretics, and angiotensin-converting enzyme inhibitor or 59±31mg (range 20–150mg) for bevantolol, and 18±7mg angiotensin II type 1 receptor antagonist for at least 3 (range 10–40mg) for carvedilol. months. The study population consisted of 67 patients (mean age 55±15, range 18–85 years) and DCM was diag- Echocardiographic Study nosed in all patients according to the criteria of the World M-mode and 2-dimensional echocardiographic studies Health Organization/International Society and Federation were performed with an Aloka SSD 9000 or SSD 5500 of Cardiology definition of cardiomyopathies.8 All patients imaging system (Tokyo, Japan) equipped with a 2.5- or underwent coronary angiography, and patients with coro- 3.5-MHz transducer. The M-mode echocardiogram was nary artery disease were excluded from this study. Patients recorded on a strip-chart recorder at a paper speed of were also excluded if they had obstructive lung disease, 50mm/s or 100mm/s. The following conventional varia- bronchial asthma or symptomatic peripheral vascular bles were obtained from the M-mode measurements disease. The Human Investigations Committee of the insti- according to the criteria of the American Society of Echo- cardiography:9 left ventricular dimension at end diastole (Received April 21, 2003; revised manuscript received July 7, 2003; (LVDd), and end systole (LVDs), left ventricular volume accepted July 16, 2003) calculated using Teichholtz’s formula and ejection fraction The Second Department of Internal Medicine, Ehime University (LVEF). Arterial blood pressure was determined in dupli- School of Medicine, Ehime, Japan Mailing address: Yuji Hara, MD; The Second Department of Internal cate on the day of the echocardiographic studies using a Medicine, Ehime University School of Medicine, Shigenobu-cho, sphygmomanometer. Onsen-gun, Ehime 791-0295, Japan. E-mail: [email protected]. ac.jp

Circulation Journal Vol.67, October 2003 Beta-Blocker Therapy in Elderly DCM Patients 827

Measurement of Plasma Concentrations of Atrial and Table 1 Clinical Characteristics and Hemodynamic Data Brain Natriuretic Peptide of the Subgroups Plasma concentrations of atrial and brain natriuretic ≥65 <65 peptide (ANP and BNP) were determined as reported pre- (n=20) (n=47) viously.10 A blood sample was taken from the antecubital Mean age (years) 72±5 48±11* vein in the morning after 30min of supine rest and imme- M/F 15:5 41:6 diately transferred into chilled glass tubes containing NYHA functional calss (n) disodium ethylenediaminetetraacetic acid (1 mg/ml) and I 2 4 aprotinin (500 U/ml). The samples were centrifuged at II 10 30 3,000rpm for 10min at 4°C and the plasma was frozen and III 7 13 stored at –80°C until radioimmunoassay (RIA) of ANP IV 1 0 BMI 21.7±2.2 23.7±4.9 (Shiono RIA assay kit, Shionogi Co, Ltd, Osaka, Japan) Concomitant medications (n) and BNP (S-1215, Shionogi Co, Ltd) was performed. The Furosemide 19 (95%) 39 (83%) normal values in the laboratory are <43.0pg/ml for plasma Spironolactone 14 (70%) 28 (60%) ANP and <17.0pg/ml for plasma BNP. Digoxin 13 (65%) 20 (43%) ACEI or ARB 19 (95%) 43 (91%) Statistical Analysis Atrial fibrillation (n) 6 (30%) 8 (17%) HR (/min) 74±18 76±14 Data are presented as mean±SD. Baseline characteris- SBP (mmHg) 120±15 113±12 tics, except for natriuretic peptides, were analyzed with an unpaired t-test or chi-square test (for nonparametrically *p<0.0001 vs ≥65. distributed values). Between-group differences in natri- NYHA, New York Heart Association; BMI, body mass index; ACEI, angio- uretic peptides were tested by Wilcoxon’s signed rank test. tensin-converting enzyme inhibitor; ARB, angiotensin II type 1 receptor Changes in the hemodynamic and echocardiographic varia- antagonist; HR, heart rate; SBP, systolic blood pressure. bles afterβ-blocker therapy were analyzed using Student’s paired t-test, and changes in New York Heart Association (NYHA) functional class and natriuretic peptides were ol, and in the older group they were 31±15mg, 52±29 and determined by the Wilcoxon’s signed rank test. All calcula- 16±4mg, respectively. The mean period until the mainte- tions were performed on a personal computer with the nance dose was attained in the younger and older groups statistical package StatView (1994; Abacus Concepts Inc, was 44±24 and 43±26 days, respectively. Differences in Berkeley, CA, USA). A value of p<0.05 was considered mean β-blocker dose and the mean period until mainte- significant. nance dose was achieved were not significant between the 2 groups.

Results Hemodynamics and Cardiac Function and Natriuretic Clinical Characteristics of the 2 Groups at Baseline Peptides in the 2 Groups Before and After Treatment The study group was divided into 20 older patients (≥65 Although there were no significant differences in heart years of age: older group) and 47 younger ones (<65 years rate, systolic blood pressure, LVDd or LVDs between the 2 of age: younger group). When the clinical characteristics groups at the start of the study, plasma concentrations of were evaluated at the start of the study, no significant dif- ANP and BNP were significantly greater in the older group ferences were found between the 2 groups in gender, than in the younger group (ANP: p=0.0455, BNP: p= NYHA functional class, concomitant medications, and 0.0415). Afterβ-blocker treatment, the NYHA functional number of atrial fibrillations (Table1). class significantly decreased in both groups (older group: from 2.35±0.75 to 1.80±0.62, p=0.0051; younger group: Tolerance and Maintenance Doses of the 2 Groups from 2.35±0.75 to 1.80±0.62, p<0.0001). Although systolic All patients tolerated β-blocker therapy. Mean mainte- blood pressure was not significantly changed in both groups nance doses in the younger group were 40±16mg for meto- (older group: from 120±15 to 119±14; younger group: prolol, 65±33mg for bevantolol, and 19±7mg for carvedil- from 113±12 to 116±16), heart rate was significantly de-

Fig1. Changes in LVDd (Left), LVDs (Middle) and EF (Right) from the start of treatment to 6 months later in the older group and younger group.

Circulation Journal Vol.67, October 2003 828 HARA Y et al.

Fig2. Changes in ANP (Left) and BNP (Right) from the start of treatment to 6 months later in the older group and younger group. creased in both groups byβ-blocker treatment (older group: whereas the younger ones had increases of 7.8%. In the from 74±18 to 62±10 beats/min; younger group: from present study, no significant difference in the improvement 76±14 to 66±9beats/min). Fig1 shows the changes in car- of cardiac function was shown between older and younger diac function, and Fig2 shows the changes in the natriure- groups, so we believe that β-blocker therapy improves tic peptides in the 2 groups. Afterβ-blocker treatment, both cardiac function in elderly patients with DCM to the same LVDd and LVDs significantly decreased and LVEF signifi- extent as in younger patients with DCM. cantly increased in both groups. There was no significant In this study, concentrations of natriuretic peptides were difference in the changes of the LVEF between the 2 attenuated by β-blocker therapy in both groups, but the groups (older group: 8.7±7.8; younger group: 7.3±9.2). concentrations were significantly higher in the older group Although the plasma concentrations of ANP and BNP were both before and afterβ-blocker treatment. Previous studies significantly decreased in both groups, they remained have reported that the concentrations of natriuretic peptides significantly greater in the older group than in the younger increase with advancing age,16–18 and although the mecha- group, even at the end of treatment (ANP: p=0.0037; BNP: nisms for this are unclear, these investigators suggested p=0.0030). age-related changes in systolic blood pressure, cardiovas- cular comorbidity, left ventricular mass, diastolic function or renal function. Although we did not examine renal func- Discussion tion, the difference in the natriuretic peptide concentrations The present study confirms that older patients with DCM between the 2 groups may have been caused by age-related tolerate β-blocker therapy and that the effects of this alterations in systolic blood pressure or renal function. therapy on cardiac function are similar in both older and younger patients. Study Limitations Previous studies reported that fibrotic changes in the The protocol was not randomized and the researchers sinus node are related to age and that responsiveness of the were not blinded to treatment; however, the measurements β-adrenoceptor diminishes with advancing age.11–13 In the of cardiac function and natriuretic peptides were performed present study, the maintenance doses were determined on in a blinded manner with regard to groups and time. the basis of one of 3 end-points, decrease in systolic blood Second, we used three kinds of β-blocker; metoprolol, pressure, decrease in heart rate at rest, or clinical deteriora- bevantolol and carvedilol. However, we have previously tion and these may be the reason why heart rate did not dif- reported that bevantolol showed parallel beneficial effects fer significantly between the younger and the older groups to those of metoprolol on cardiac function and natriuretic at the end of treatment. However, the decline in heart rate peptides in patients with DCM.19 The third limitation is the was similar in both groups and so the effectiveness ofβ- small number of study patients, which meant we could not blockers is likely to be similar in both groups. compare the effect of 3 differentβ-blockers. We are aware Waagstein et al reported that treatment with metoprolol that a larger number of subjects would improve the reliabil- was useful for patients with DCM, but the mean age of ity and impact of our results. their patients was 49 years.2 Packer et al14 and Aranda et In conclusion, both older and younger patients with al15 reported thatβ-blocker therapy was beneficial in older DCM can tolerate and respond well to β-blocker therapy patients (>65 years old) with heart failure. Aranda et al and we suggest thatβ-blockers may be a beneficial adjunct reported that both elderly (>65 years old) and younger (<65 to the treatment regime of elderly patients with DCM. years old) patients with heart failure can safely tolerateβ- blocker (bucindolol) therapy and their physiologic and References hemodynamic responses toβ-blocker therapy were similar, 1. Waagstein F, Hjalmarson Å, Varnaukas E, Wallentin I. Effect of although the younger patients had a greater improvement in chronic beta-adrenergic receptor blockade in congestive cardiomyo- LVEF than the older ones.15 That finding may be related to pathy. Br Heart J 1975; 37: 1022–1036. the lower heart rate in older patients, which means the ratio 2. Waagstein F, Bristow MR, Swedberg K, Camerini F, Fowler MB, Silver MA, et al. Beneficial effects of metoprolol in idiopathic to achieve target dose was lower in the older patients than dilated cardiomyopathy. Lancet 1993; 342: 1441–1446. in the younger patients. However, similar to our findings, 3. Krum H, Sackner-Bernstein JD, Goldsmith RL, Kukin ML, Schwartz their older patients showed increases of 6.5% in LVEF, B, Penn J, et al. Double-blind, placebo-controlled study of the long-

Circulation Journal Vol.67, October 2003 Beta-Blocker Therapy in Elderly DCM Patients 829

term efficacy of carvedilol in patients with severe chronic heart fail- 11. Vestal RE, Wood AJ, Shand DG. Reduced beta-adrenoceptor sensi- ure. Circulation 1995; 92: 1499–1506. tivity in the elderly. Clin Pharmacol Ther 1979; 26: 181–186. 4. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert 12. Fleg JL, Schulman S, O’Connor F, Becker LC, Gerstenblith G, EM, et al. The effect of carvedilol on morbidity and mortality in Clulow JF, et al. Effects of acute beta-adrenergic receptor blockade patients with chronic heart failure. N Engl J Med 1996; 334: 1349– on age-associated changes in cardiovascular performance during 1355. dynamic exercise. Circulation 1994; 90: 2333–2341. 5. CIBIS II Investigators and Committees. The cardiac insufficiency 13. Taneja T, Mahnert BW, Passman R, Goldberger J, Kadish A. Effects bisoprolol study II (CIBIS-II): A randomised trial. Lancet 1999; 353: of sex and age on electrocardiographic and cardiac electrophysiolog- 9–13. ical properties in adults. Pacing Clin Electrophysiol 2001; 24: 16– 6. Hirooka K, Yasumura Y, Ishida Y, Hanatani A, Nakatani S, 21. Komamura K, et al. Comparative left ventricular functional and 14. Packer M, Coats AJS, Fowler MB, Katus HA, Krum H, Mohacsi P, neurohormoral effects of chronic treatment with carvedilol versus et al. Effect of carvedilol on survival in severe chronic heart failure. metoprolol in patients with dilated cardiomyopathy. Jpn Circ J 2001; N Engl J Med 2001; 344: 1651–1658. 65: 931–936. 15. Aranda JM, Krause-Steinrauf HJ, Greenberg BH, Heng MK, 7. Hara Y, Hamada M, Ohtsuka T, Ogimoto A, Saeki H, Suzuki J, et al. Kosolcharoen PK, Renlund DG, et al. Comparison of the beta Use of thallium-201 myocardial scintigraphy for prediction of the blocker bucindolol in younger vs older patients with heart failure. response toβ-blocker therapy in patients with dilated cardiomyopa- Am J Cardiol 2002; 89: 1322–1326. thy. Circ J 2002; 66: 1139–1143. 16. Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey 8. Report of the 1995 World Health Organization/International Society KR, Burnett JC Jr. Plasma brain natriuretic peptide concentration: and Federation of Cardiology task force on the definition and classifi- Impact of age and gender. J Am Coll Cardiol 2002; 40: 976–982. cation of cardiomyopathies. Circulation 1996; 93: 841–842. 17. Davis KM, Fish LC, Minaker KL, Elahi D. Atrial natriuretic peptide 9. Sahn DJ, DeMaria A, Kisslo J, Weyman A. The Committee on M- levels in the elderly: Differentiating normal aging changes from mode Standardization of The American Society of Echocardiogra- disease. J Gerontol A Biol Sci Med Sci 1996; 51: M95–M101. phy. Recommendations regarding quantitation in M-mode echocar- 18. Sayama H, Nakamura Y, Saito N, Kinoshita M. Why is the concen- diography: Results of a survey of echocardiographic measurements. tration of plasma brain natriuretic peptide in elderly inpatients Circulation 1978; 58: 1072–1083. greater than normal? Coron Artery Dis 1999; 10: 537–540. 10. Hamada M, Shigematsu Y, Kawakami H, Minamino N, Kangawa K, 19. Hara Y, Hamada M, Ohtsuka T, Ogimoto A, Saeki H, Matsunaka T, Matsuo H, et al. Increased plasma levels of adrenomedullin in pa- et al. Comparison of treatment effects of bevantolol and metoprolol tients with hypertrophic cardiomyopathy: Its relation to endothelin-1, on cardiac function and natriuretic peptides in patients with dilated natriuretic peptides and noradrenaline. Clin Sci 1998; 94: 21–28. cardiomyopathy. Heart Vessel 2002; 17: 53–56.

Circulation Journal Vol.67, October 2003