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Effects of β-blockers on left ventricular remodeling in patients with preserved ejection fraction after acute myocardial infarction
International Journal of Cardiology 221 (2016) 765–769
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Effects of β-blockers on left ventricular remodeling in patients with preserved ejection fraction after acute myocardial infarction☆ Yu Horiuchi a, Shuzou Tanimoto a,⁎, Jiro Aoki a, Hiroyoshi Nakajima b, Kazuhiro Hara c, Kengo Tanabe a a b c
Division of Cardiology, Mitsui Memorial Hospital, Tokyo, Japan Division of General Medicine, Mitsui Memorial Hospital, Tokyo, Japan Division of Internal Medicine, Mitsui Memorial Hospital, Tokyo, Japan
a r t i c l e
i n f o
Article history: Received 18 May 2016 Accepted 8 July 2016 Available online 09 July 2016 Keywords: β-Blocker Acute myocardial infarction Heart failure with preserved ejection fraction
a b s t r a c t Background: The effects of β-blockers on left ventricular (LV) remodeling have been established in patients with reduced ejection fraction (EF) after acute myocardial infarction (AMI). In AMI patients with preserved EF, additional effects of β-blockers on reperfusion therapy and current medical treatment have not been elucidated. Methods: Patients with preserved EF (≥ 40%), who underwent percutaneous coronary intervention (PCI) for AMI and obtained complete coronary revascularization were enrolled retrospectively. These were divided into groups treated with or without β-blockers at discharge. Echocardiography was performed on admission and 8 months after PCI to observe LVEF, LV end diastolic volume index (LVEDVI), LV end systolic volume index (LVESVI), LV end diastolic diameter (LVDd), and LV end systolic diameter (LVDs). Results: A total of 114 patients were enrolled; 81 were treated with β-blockers (β-blocker group) and 33 were treated without β-blockers (non-β-blocker group). All patients were prescribed antiplatelets and 96% took either an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker. At followup, EF improved in both groups (2.6% in the β-blocker group and 4.6% in the non-β-blocker group). In the β-blocker group, neither LVEDVI nor LVESVI decreased. However, both LVEDVI (− 4.3 ml/m2) and LVESVI (− 4.1 ml/m2) improved in the non-β-blocker group. There were significant increases in LVDd (2.1 mm) and LVDs (2.2 mm) in the β-blocker group, whereas these parameters did not significantly change in the non-β-blocker group. Conclusions: Effects of β-blockers on LV remodeling were uncertain in AMI patients with preserved EF, who obtained complete coronary revascularization and received optimal medical treatment. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The effects of β-blocker therapy after acute myocardial infarction (AMI) are well established, and their administration is universally recommended by several guidelines [1–3]. Because much of the evidence to support the beneficial effects of β-blockers in AMI patients antedates current standard therapy, the efficacy of β-blockers has been investigated in the reperfusion era. The beneficial effects of β-blockers in AMI patients with systolic dysfunction (ejection fraction [EF] ≤ 40%) were determined in the Carvedilol Post-Infarct Survival Control in LV Dysfunction (CAPRICORN) randomized trial [4], which demonstrated that carvedilol reduced all-cause and cardiovascular mortality, and recurrent
☆ These authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Division of Cardiology, Mitsui Memorial Hospital, KandaIzumi-cho 1, Chiyoda-ku, Tokyo 101-8643, Japan. E-mail address: [email protected] (S. Tanimoto).
http://dx.doi.org/10.1016/j.ijcard.2016.07.123 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
nonfatal MI. These effects were additive to reperfusion therapy and angiotensin-converting enzyme inhibitors (ACE-I). The effects of β-blockers on heart failure (HF) were also investigated in the CAPRICORN Echo substudy [5]. In the carvedilol group, left ventricular (LV) EF increased and LV end systolic volume index (LVESVI) decreased significantly compared to the placebo group. These results demonstrated the beneficial effects of β-blockers in inhibiting progressive LV remodeling, which is one of the most important indicators of HF progression and poor prognosis [6–8]. However, these relationships have not been fully elucidated in AMI patients with preserved EF. It is unclear whether there is a remaining opportunity for a β-blocker to add beneficial effects for LV remodeling in AMI patients with preserved EF, who have little ischemic insult due to primary reperfusion therapy and are receiving current medical treatment including renin–angiotensin–aldosterone system blockade. The aim of the study was to investigate the effects of β-blockers on LV remodeling in AMI patients with preserved EF, who underwent reperfusion therapy and optimal medical treatment.
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Fig. 1. Study flowchart. 2. Methods All AMI patients who underwent percutaneous coronary intervention (PCI) at our institution were retrospectively evaluated. These patients underwent echocardiography on admission and 8 months after PCI. Patients with preserved EF (≥40%) on admission were eligible for the study. Of these, patients who obtained complete coronary revascularization were enrolled in order to avoid discussion about effects of β-blockers on residual ischemia. Patients without follow-up echocardiography were excluded. We observed whether they were treated with or without β-blockers at discharge and divided these patients into two groups: β-blocker and non-β-blocker. Medication type (either carvedilol or bisoprolol), starting timing and dose, and titration of β-blockers were at the physician's discretion. Patient characteristics and changes in echocardiographic data were analyzed in both groups. The study was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent, and all data were anonymized throughout the study and analysis. AMI was defined as detection of a rise in troponin above the 99th percentile of the upper reference limit, and with at least one of the following: symptoms of ischemia; new or presumably new significant ST-T changes or new left bundle branch block; development of pathological Q waves in the electrocardiogram; and imaging evidence of new loss of viable myocardium, or new regional wall motion abnormality, or identification of an intracoronary thrombus by angiography [2]. Following the guidelines, PCI was performed as early as possible in AMI patients with ST-segment elevation [2], and was performed after rapid risk stratification in AMI patients without ST-segment elevation [3]. Complete revascularization refers to complete anatomic revascularization, which means all stenotic main-branch vessels are revascularized [9]. Patient characteristics were collected on admission. Risk factors for cardiovascular disease, including age, sex, hypertension (blood pressure ≥ 140/90 mm Hg and/or the use of antihypertensive medications), smoking (current smoker), dyslipidemia (fasting serum low-density lipoprotein cholesterol ≥140 mg/dl, high-density lipoprotein cholesterol b40 mg/dl, or triglyceride ≥150 mg/dl, and/or the use of medications for dyslipidemia), family history of coronary artery disease (CAD), diabetes mellitus (hemoglobin A1C ≥6.5% and/or the use of oral hypoglycemic agents or insulin treatment), chronic kidney disease (CKD; estimated glomerular filtration rate b60 ml/min/1.73 m2), hemodialysis, history of CAD, and atrial fibrillation were recorded. Serum creatinine level and serum brain natriuretic peptide level were obtained. We recorded ST-elevation MI (STEMI), coronary profiles, and max serum creatinine kinase level. Vital signs and medication at discharge were also recorded.
2.1. Echocardiography Echocardiography (Phillips CX50, Philadelphia, PA, USA) was performed on admission and 8 months after PCI to observe LVEF, LV end diastolic volume index (LVEDVI), LVESVI, LV end diastolic diameter (LVDd), and LV end systolic diameter (LVDs). These calculations were performed according to the recommendations for chamber quantification by the American Society of Echocardiography [10]. LVEF was calculated by the modified Simpson method. We also evaluated parameters of LV diastolic function (deceleration time and e′) and filling pressures (E/e′). Ultrasonographers performed echocardiography and specialists of the Japanese Society of Echocardiography approved the findings. Both ultrasonographers and echocardiography specialists were blinded to patient background and treatment.
2.2. Statistics Quantitative variables were described as mean ± standard deviation or median (interquartile range), and qualitative variables were described as number and percentage. Paired t-test and/or Wilcoxon's test were used to evaluate the serial changes of vital signs and echocardiography data in each group. ANCOVA test was used to evaluate the changes of these data between the two groups. Results were considered statistically significant at p b 0.05. All statistical analyses were performed by using JMP version 12.0.1 for Windows (SAS, North Carolina, USA).
Table 1 Patient characteristics. Characteristics
β-Blocker group (n = 81)
Non-β-blocker group (n = 33)
p value
Age (y) Male gender Hypertension Current smoker Dyslipidemia Family history Diabetes mellitus CKD Hemodialysis Previous MI Previous PCI Previous CABG Atrial fibrillation Creatinine (mg/dl) Log BNP (pg/ml) STEMI Coronary profile Multi-vessel disease Max creatinine kinase (IU/l) Vital signs at discharge Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (bpm) Echocardiography data LVEF (%) LVEDVI (ml/m2) LVESVI (ml/m2) LVDd (mm) LVDs (mm) Deceleration time (ms) e′ (cm/s) E/e′ Medications at discharge Aspirin Statin ACE-inhibitor ARB ACE-inhibitor or ARB Furosemide Nitric oxides Clinical outcomes Hospitalization for heart failure Recurrent MI
62.1 ± 12.0 65 (80%) 58 (72%) 40 (49%) 47 (58%) 20 (25%) 26 (32%) 16 (20%) 3 (3.7%) 6 (7.4%) 7 (8.6%) 2 (2.5%) 2 (2.5%) 0.80 (0.69, 0.93) 1.62 ± 0.56 60 (74%)
62.0 ± 13.3 27 (82%) 21 (64%) 15 (45%) 18 (55%) 8 (24%) 11 (33%) 7 (21%) 2 (6.1%) 3 (9.1%) 4 (12%) 1 (3.0%) 2 (6.1%) 0.83 (0.68, 1.00) 1.65 ± 0.70 19 (58%)
0.94 1.00 0.50 0.84 0.84 1.00 1.00 1.00 0.63 0.72 0.73 1.00 0.58 0.51 0.78 0.12
32 (40%) 1837 (530, 4058)
13 (39%) 468 (111, 1268)
1.00 b0.01
114 ± 16.2 67.7 ± 12.3 64.8 ± 9.9
116 ± 17.7 68.2 ± 15.6 66.5 ± 8.0
0.63 0.87 0.39
57.0 ± 7.0 52.3 ± 13.7 22.8 ± 7.9 46.1 ± 5.5 29.9 ± 4.8 193 ± 47.2 5.9 ± 2.0 11.8 ± 3.7
59.2 ± 8.8 51.1 ± 10.6 21.3 ± 7.8 46.6 ± 3.3 30.6 ± 3.9 184 ± 41.8 6.0 ± 1.3 11.9 ± 3.1
0.16 0.66 0.35 0.53 0.46 0.36 0.84 0.82
81 (100%) 79 (98%) 73 (90%) 4 (5%) 77 (95%) 4 (5%) 43 (53%)
33 (100%) 33 (100%) 31 (94%) 1 (3%) 32 (97%) 1 (3%) 13 (39%)
NA 1.00 0.72 1.00 1.00 1.00 0.22
4 (5%) 0 (0%)
1 (3%) 0 (0%)
1.00 NA
ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blocker; BNP, brain natriuretic peptide; CABG, coronary artery bypass grafting; CKD, chronic kidney disease; LVDd, left ventricular diastolic diameter; LVDs, left ventricular systolic diameter; LVEDVI, left ventricular end diastolic volume index; LVEF, left ventricular ejection fraction; LVESVI, left ventricular end systolic volume index; MI, myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction.
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Fig. 2. Changes in vital signs between admission and follow-up. A. Changes in systolic blood pressure between admission and follow-up. B. Changes in diastolic blood pressure between admission and follow-up. C. Changes in heart rate between admission and follow-up.
3. Results From January 2012 to December 2013, 250 AMI patients underwent PCI at our institution. Of these, 216 patients had preserved EF. Eightythree patients without follow-up echocardiography and 19 patients without complete revascularization were excluded. A total of 114 AMI patients were enrolled (Fig. 1). 3.1. Patient characteristics The characteristics of the study populations are shown in Table 1. Eighty-one patients (71%) were treated with β-blockers at discharge: carvedilol in 62 patients and bisoprolol in 19 patients. Mean length of β-blocker therapy was 233 ± 33 days. Mean doses of β-blocker at follow-up were 4.1 ± 2.9 mg for carvedilol and 2.8 ± 1.7 mg for bisoprolol. Patient demographics, concomitant disease, past medical history, and laboratory data on admission including brain natriuretic peptide were not different between the two groups. In the β-blocker group, STEMI was more frequently observed and max creatinine kinase was significantly higher than in the non-β-blocker group. Vital signs at discharge were similar between the two groups. With regard to echocardiography data, LVEF was lower in the β-blocker group than in the non-β-blocker group, although these differences did not reach statistical significance. Other echocardiography data on admission were not different between the two groups. All patients took antiplatelet agents. Statins were prescribed in 98%, and 96% were treated with either an ACE-I or angiotensin II receptor blocker (ARB). During followup, frequency of hospitalization for HF was not different between the two groups (5% in the β-blocker group and 3% in the non-β-blocker group, p = 1.00), and recurrent MI was not observed in either group. 3.2. Changes in vital signs Fig. 2 shows changes in blood pressure (BP) and heart rate (HR) between admission and follow-up in the two groups. Systolic BP increased in both groups (12 mm Hg, 95% CI 8.3 to 16, p b 0.01 in the β-blocker group, and 9.1 mm Hg, 95% CI 2.2 to 16, p = 0.01 in the non-βblocker group, respectively) (Fig. 2A). Diastolic BP also increased in both groups (6.9 mm Hg, 95% CI 3.4 to 10, p b 0.01 in the β-blocker group, and 5.2 mm Hg, 95% CI 0.91 to 9.5, p = 0.02 in the non-βblocker group, respectively) (Fig. 2B). HR decreased in both groups
(− 3.0 bpm, 95% CI − 5.5 to − 0.41, p = 0.02, and − 3.6 bpm, 95% CI −7.1 to −0.07, p = 0.05) (Fig. 2C). 3.3. Changes in echocardiography data Changes in echocardiography data between admission and followup are shown in Fig. 3. LVEF improved in both groups (2.6%, 95% CI 0.87 to 4.3, p b 0.01 in the β-blocker group, and 4.6%, 95% CI 1.9 to 7.4, p b 0.01 in the non-β-blocker group, respectively) (Fig. 3A). Both LVEDVI and LVESVI did not significantly change in the β-blocker group, while both LVEDVI and LVESVI significantly decreased in the non-β-blocker group (LVEDVI: − 4.3 ml/m2, 95% CI − 8.2 to − 0.48, p = 0.03, and LVESVI: − 4.1 ml/m2, 95% CI − 6.3 to − 1.8, p b 0.01) (Fig. 3B, C). There were significant increases of both LVDd and LVDd in the β-blocker group (LVDd: 2.1 mm, 95% CI 1.2 to 2.9, p b 0.01, and LVDs: 2.2 mm, 95% CI 1.3 to 3.2, p b 0.01), while there were no significant changes in both LVDd and LVDs in the non-β-blocker group (Fig. 3D, E). Deceleration time improved in the two groups (35 ms, 95% CI 22 to 48, p b 0.01 in the β-blocker group, and 56 ms, 95% CI 32 to 80, p b 0.01 in the non-β-blocker group, respectively). e′ and E/e′ did not significantly change in the β-blocker group (e′: 0.22 cm/s, 95% CI − 0.24 to 0.68, p = 0.34, and E/e′: − 0.64, 95% CI − 1.6 to 0.31, p = 0.19), while these data significantly improved in the non-β-blocker group (e′: 0.49 cm/s, 95% CI 0.02 to 0.97, p = 0.04, and E/e′: −1.8, 95% CI −2.7 to −0.90, p b 0.01). 4. Discussion The present study showed that the effects of β-blockers on LV remodeling were uncertain in AMI patients with preserved EF who obtained complete coronary revascularization and optimal medical treatments. Although EF improved in the β-blocker group, neither LVEDVI nor LVESVI decreased, and LV diameters increased between admission and follow-up. The beneficial effects of β-blocker on LV remodeling have not been fully elucidated in AMI patients with preserved EF. In the present study, all patients underwent PCI to limit the initial insult of AMI, which is the most effective way to prevent or minimize post-MI cardiac remodeling [11]. These patients also underwent complete coronary revascularization to eliminate the residual ischemic burden. Most patients were treated with an ACE-I or ARB, which are also related to inhibition of LV remodeling. [12,13]. In the β-blocker group, additive beneficial
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Fig. 3. Changes in echocardiography data between admission and follow-up. A. Changes in left ventricular ejection fraction between admission and follow-up. B. Changes in left ventricular end diastolic volume index between admission and follow-up. C. Changes in left ventricular end systolic volume index between admission and follow-up. D. Changes in left ventricular end diastolic diameter between admission and follow-up. E. Changes in left ventricular end systolic diameter between admission and follow-up.
effects of β-blockers were expected to ameliorate LV remodeling. Although EF improved at follow-up in the β-blocker group, neither LVEDVI nor LVESVI improved. LVESV is the most important predictor of prognosis after AMI [14]. Moreover, LV diameters significantly deteriorated rather than improved. In the present study, effects of β-blockers on LV remodeling were uncertain in AMI patients with preserved EF. There could be several reasons for this result. First, in the β-blocker group, STEMI was more frequently observed and max creatinine kinase was significantly higher than in the non-βblocker group. Patients treated with β-blockers could have severe cardiovascular status preventing LV remodeling. However, beneficial effects of β-blockers have been demonstrated in patients with much worse cardiac conditions. As mentioned above, in the CAPRICORN Echo substudy, β-blockers improved LV remodeling in patients with reduced EF [5]. These patients were complicated with more severe ischemic insults compared to the AMI patients with preserved EF. The effects of β-blockers have also been demonstrated in HF patients with very low EF (b 25%) and severe symptoms [15].
Second, the mean dose of β-blockers was relatively lower in the present study than in prior studies. β-Blockers were reported to show dose-related improvement in HF and LVEF [16,17]. On the other hand, in other studies, these relationships were not demonstrated and low dose β-blocker therapy produced important clinical benefit [18,19]. In addition, in the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure (SENIORS) echocardiographic substudy, in which the effect of nebivolol on LV function was observed, neither LVEF, LVEDV, nor LVESV improved in patients with LVEF ≥35% despite a maintenance dose level reached of ≥5 mg in 79.6% of the patients in the study cohort [20]. The relationships between change in HR and LVEF as well as HF prognosis are another aspect of β-blocker therapy currently being investigated. In meta-analysis of patients with systolic HF, a close relationship between a decrease in HR and increase in LVEF was observed [21]. A decrease in HR was also related to improvement in HF prognosis in systolic HF patients [21,22]. In the present study, decrease in HR and improvement of EF were observed in both groups. However, in the β-blocker group, whether
Y. Horiuchi et al. / International Journal of Cardiology 221 (2016) 765–769
these favorable changes in HR and LVEF can lead to improvement in HF prognosis is unclear because LVESV, which is the most important predictor of prognosis after AMI [14], did not improve. These results were consisted with the fact that the role of β-blockers in HF with preserved EF has not been fully elucidated [23]. Third, β-blockers have recently been reported to be a risk factor for HF in post-AMI patients. In meta-analysis, Bangalore et al. reported that β-blockers improved mortality in the pre-reperfusion era, while no mortality benefit was observed in the reperfusion era in AMI patients [24]. In the reperfusion era, although β-blockers reduced recurrent MI and angina, the clinical benefit lasted for only 30 days. Moreover, β-blocker therapy increased the rate of HF. Bao et al. reported that in STEMI patients who underwent PCI, β-blockers were not associated with favorable clinical outcomes. In patients with reduced EF, the risk for mortality, MI, and hospitalization for HF were not different among the patients with or without β-blockers. In patients with preserved EF, hospitalization for HF was significantly higher in patients with β-blockers compared to patients without β-blockers after potential confounders were adjusted [25]. The results of the present study and these reports suggest that beneficial effects of β-blockers on HF after AMI are unclear in the reperfusion era, especially in patients with preserved EF. Several potential limitations exist in this study. Class effects of β-blockers were not observed. Both carvedilol and bisoprolol were evaluated at the same time. We do not have information about the timing of titration of β-blockers after discharge. This is a single center observational study and selection bias for the use of β-blockers is inevitable. In conclusion, the effects of β-blockers on LV remodeling were uncertain in AMI patients with preserved EF who obtained complete coronary revascularization and optimal medical treatment. Largescale randomized controlled study is warranted to elucidate the effects of β-blockers on HF in AMI patients with preserved EF in the reperfusion era. Disclosure Kengo Tanabe, remuneration (Abbott Vascular, Terumo, Kaneka, Zeon, Sanofi, Daiichi-Sankyo, Tanabe-Mitsubishi). Acknowledgement of grant support None. References [1] T.D. Fraker Jr., S.D. Fihn, R.J. Gibbons, et al., 2007 chronic angina focused update of the ACC/AHA 2002 guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association task force on practice guidelines writing group to develop the focused update of the 2002 guidelines for the management of patients with chronic stable angina, Circulation 116 (23) (2007) 2762–2772. [2] Task force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC), S. PG, J. SK, et al., 2012 ESC guidelines on acute myocardial infarction (STEMI), Eur. Heart J. 33 (20) (2012) 2569–2619. [3] C.W. Hamm, J.P. Bassand, S. Agewall, et al., ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the task force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC), Eur. Heart J. 32 (23) (2011) 2999–3054.
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Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Effects of β-blockers on left ventricular remodeling in patients with preserved ejection fraction after acute myocardial infarction☆ Yu Horiuchi a, Shuzou Tanimoto a,⁎, Jiro Aoki a, Hiroyoshi Nakajima b, Kazuhiro Hara c, Kengo Tanabe a a b c
Division of Cardiology, Mitsui Memorial Hospital, Tokyo, Japan Division of General Medicine, Mitsui Memorial Hospital, Tokyo, Japan Division of Internal Medicine, Mitsui Memorial Hospital, Tokyo, Japan
a r t i c l e
i n f o
Article history: Received 18 May 2016 Accepted 8 July 2016 Available online 09 July 2016 Keywords: β-Blocker Acute myocardial infarction Heart failure with preserved ejection fraction
a b s t r a c t Background: The effects of β-blockers on left ventricular (LV) remodeling have been established in patients with reduced ejection fraction (EF) after acute myocardial infarction (AMI). In AMI patients with preserved EF, additional effects of β-blockers on reperfusion therapy and current medical treatment have not been elucidated. Methods: Patients with preserved EF (≥ 40%), who underwent percutaneous coronary intervention (PCI) for AMI and obtained complete coronary revascularization were enrolled retrospectively. These were divided into groups treated with or without β-blockers at discharge. Echocardiography was performed on admission and 8 months after PCI to observe LVEF, LV end diastolic volume index (LVEDVI), LV end systolic volume index (LVESVI), LV end diastolic diameter (LVDd), and LV end systolic diameter (LVDs). Results: A total of 114 patients were enrolled; 81 were treated with β-blockers (β-blocker group) and 33 were treated without β-blockers (non-β-blocker group). All patients were prescribed antiplatelets and 96% took either an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker. At followup, EF improved in both groups (2.6% in the β-blocker group and 4.6% in the non-β-blocker group). In the β-blocker group, neither LVEDVI nor LVESVI decreased. However, both LVEDVI (− 4.3 ml/m2) and LVESVI (− 4.1 ml/m2) improved in the non-β-blocker group. There were significant increases in LVDd (2.1 mm) and LVDs (2.2 mm) in the β-blocker group, whereas these parameters did not significantly change in the non-β-blocker group. Conclusions: Effects of β-blockers on LV remodeling were uncertain in AMI patients with preserved EF, who obtained complete coronary revascularization and received optimal medical treatment. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The effects of β-blocker therapy after acute myocardial infarction (AMI) are well established, and their administration is universally recommended by several guidelines [1–3]. Because much of the evidence to support the beneficial effects of β-blockers in AMI patients antedates current standard therapy, the efficacy of β-blockers has been investigated in the reperfusion era. The beneficial effects of β-blockers in AMI patients with systolic dysfunction (ejection fraction [EF] ≤ 40%) were determined in the Carvedilol Post-Infarct Survival Control in LV Dysfunction (CAPRICORN) randomized trial [4], which demonstrated that carvedilol reduced all-cause and cardiovascular mortality, and recurrent
☆ These authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Division of Cardiology, Mitsui Memorial Hospital, KandaIzumi-cho 1, Chiyoda-ku, Tokyo 101-8643, Japan. E-mail address: [email protected] (S. Tanimoto).
http://dx.doi.org/10.1016/j.ijcard.2016.07.123 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
nonfatal MI. These effects were additive to reperfusion therapy and angiotensin-converting enzyme inhibitors (ACE-I). The effects of β-blockers on heart failure (HF) were also investigated in the CAPRICORN Echo substudy [5]. In the carvedilol group, left ventricular (LV) EF increased and LV end systolic volume index (LVESVI) decreased significantly compared to the placebo group. These results demonstrated the beneficial effects of β-blockers in inhibiting progressive LV remodeling, which is one of the most important indicators of HF progression and poor prognosis [6–8]. However, these relationships have not been fully elucidated in AMI patients with preserved EF. It is unclear whether there is a remaining opportunity for a β-blocker to add beneficial effects for LV remodeling in AMI patients with preserved EF, who have little ischemic insult due to primary reperfusion therapy and are receiving current medical treatment including renin–angiotensin–aldosterone system blockade. The aim of the study was to investigate the effects of β-blockers on LV remodeling in AMI patients with preserved EF, who underwent reperfusion therapy and optimal medical treatment.
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Fig. 1. Study flowchart. 2. Methods All AMI patients who underwent percutaneous coronary intervention (PCI) at our institution were retrospectively evaluated. These patients underwent echocardiography on admission and 8 months after PCI. Patients with preserved EF (≥40%) on admission were eligible for the study. Of these, patients who obtained complete coronary revascularization were enrolled in order to avoid discussion about effects of β-blockers on residual ischemia. Patients without follow-up echocardiography were excluded. We observed whether they were treated with or without β-blockers at discharge and divided these patients into two groups: β-blocker and non-β-blocker. Medication type (either carvedilol or bisoprolol), starting timing and dose, and titration of β-blockers were at the physician's discretion. Patient characteristics and changes in echocardiographic data were analyzed in both groups. The study was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent, and all data were anonymized throughout the study and analysis. AMI was defined as detection of a rise in troponin above the 99th percentile of the upper reference limit, and with at least one of the following: symptoms of ischemia; new or presumably new significant ST-T changes or new left bundle branch block; development of pathological Q waves in the electrocardiogram; and imaging evidence of new loss of viable myocardium, or new regional wall motion abnormality, or identification of an intracoronary thrombus by angiography [2]. Following the guidelines, PCI was performed as early as possible in AMI patients with ST-segment elevation [2], and was performed after rapid risk stratification in AMI patients without ST-segment elevation [3]. Complete revascularization refers to complete anatomic revascularization, which means all stenotic main-branch vessels are revascularized [9]. Patient characteristics were collected on admission. Risk factors for cardiovascular disease, including age, sex, hypertension (blood pressure ≥ 140/90 mm Hg and/or the use of antihypertensive medications), smoking (current smoker), dyslipidemia (fasting serum low-density lipoprotein cholesterol ≥140 mg/dl, high-density lipoprotein cholesterol b40 mg/dl, or triglyceride ≥150 mg/dl, and/or the use of medications for dyslipidemia), family history of coronary artery disease (CAD), diabetes mellitus (hemoglobin A1C ≥6.5% and/or the use of oral hypoglycemic agents or insulin treatment), chronic kidney disease (CKD; estimated glomerular filtration rate b60 ml/min/1.73 m2), hemodialysis, history of CAD, and atrial fibrillation were recorded. Serum creatinine level and serum brain natriuretic peptide level were obtained. We recorded ST-elevation MI (STEMI), coronary profiles, and max serum creatinine kinase level. Vital signs and medication at discharge were also recorded.
2.1. Echocardiography Echocardiography (Phillips CX50, Philadelphia, PA, USA) was performed on admission and 8 months after PCI to observe LVEF, LV end diastolic volume index (LVEDVI), LVESVI, LV end diastolic diameter (LVDd), and LV end systolic diameter (LVDs). These calculations were performed according to the recommendations for chamber quantification by the American Society of Echocardiography [10]. LVEF was calculated by the modified Simpson method. We also evaluated parameters of LV diastolic function (deceleration time and e′) and filling pressures (E/e′). Ultrasonographers performed echocardiography and specialists of the Japanese Society of Echocardiography approved the findings. Both ultrasonographers and echocardiography specialists were blinded to patient background and treatment.
2.2. Statistics Quantitative variables were described as mean ± standard deviation or median (interquartile range), and qualitative variables were described as number and percentage. Paired t-test and/or Wilcoxon's test were used to evaluate the serial changes of vital signs and echocardiography data in each group. ANCOVA test was used to evaluate the changes of these data between the two groups. Results were considered statistically significant at p b 0.05. All statistical analyses were performed by using JMP version 12.0.1 for Windows (SAS, North Carolina, USA).
Table 1 Patient characteristics. Characteristics
β-Blocker group (n = 81)
Non-β-blocker group (n = 33)
p value
Age (y) Male gender Hypertension Current smoker Dyslipidemia Family history Diabetes mellitus CKD Hemodialysis Previous MI Previous PCI Previous CABG Atrial fibrillation Creatinine (mg/dl) Log BNP (pg/ml) STEMI Coronary profile Multi-vessel disease Max creatinine kinase (IU/l) Vital signs at discharge Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (bpm) Echocardiography data LVEF (%) LVEDVI (ml/m2) LVESVI (ml/m2) LVDd (mm) LVDs (mm) Deceleration time (ms) e′ (cm/s) E/e′ Medications at discharge Aspirin Statin ACE-inhibitor ARB ACE-inhibitor or ARB Furosemide Nitric oxides Clinical outcomes Hospitalization for heart failure Recurrent MI
62.1 ± 12.0 65 (80%) 58 (72%) 40 (49%) 47 (58%) 20 (25%) 26 (32%) 16 (20%) 3 (3.7%) 6 (7.4%) 7 (8.6%) 2 (2.5%) 2 (2.5%) 0.80 (0.69, 0.93) 1.62 ± 0.56 60 (74%)
62.0 ± 13.3 27 (82%) 21 (64%) 15 (45%) 18 (55%) 8 (24%) 11 (33%) 7 (21%) 2 (6.1%) 3 (9.1%) 4 (12%) 1 (3.0%) 2 (6.1%) 0.83 (0.68, 1.00) 1.65 ± 0.70 19 (58%)
0.94 1.00 0.50 0.84 0.84 1.00 1.00 1.00 0.63 0.72 0.73 1.00 0.58 0.51 0.78 0.12
32 (40%) 1837 (530, 4058)
13 (39%) 468 (111, 1268)
1.00 b0.01
114 ± 16.2 67.7 ± 12.3 64.8 ± 9.9
116 ± 17.7 68.2 ± 15.6 66.5 ± 8.0
0.63 0.87 0.39
57.0 ± 7.0 52.3 ± 13.7 22.8 ± 7.9 46.1 ± 5.5 29.9 ± 4.8 193 ± 47.2 5.9 ± 2.0 11.8 ± 3.7
59.2 ± 8.8 51.1 ± 10.6 21.3 ± 7.8 46.6 ± 3.3 30.6 ± 3.9 184 ± 41.8 6.0 ± 1.3 11.9 ± 3.1
0.16 0.66 0.35 0.53 0.46 0.36 0.84 0.82
81 (100%) 79 (98%) 73 (90%) 4 (5%) 77 (95%) 4 (5%) 43 (53%)
33 (100%) 33 (100%) 31 (94%) 1 (3%) 32 (97%) 1 (3%) 13 (39%)
NA 1.00 0.72 1.00 1.00 1.00 0.22
4 (5%) 0 (0%)
1 (3%) 0 (0%)
1.00 NA
ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blocker; BNP, brain natriuretic peptide; CABG, coronary artery bypass grafting; CKD, chronic kidney disease; LVDd, left ventricular diastolic diameter; LVDs, left ventricular systolic diameter; LVEDVI, left ventricular end diastolic volume index; LVEF, left ventricular ejection fraction; LVESVI, left ventricular end systolic volume index; MI, myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction.
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Fig. 2. Changes in vital signs between admission and follow-up. A. Changes in systolic blood pressure between admission and follow-up. B. Changes in diastolic blood pressure between admission and follow-up. C. Changes in heart rate between admission and follow-up.
3. Results From January 2012 to December 2013, 250 AMI patients underwent PCI at our institution. Of these, 216 patients had preserved EF. Eightythree patients without follow-up echocardiography and 19 patients without complete revascularization were excluded. A total of 114 AMI patients were enrolled (Fig. 1). 3.1. Patient characteristics The characteristics of the study populations are shown in Table 1. Eighty-one patients (71%) were treated with β-blockers at discharge: carvedilol in 62 patients and bisoprolol in 19 patients. Mean length of β-blocker therapy was 233 ± 33 days. Mean doses of β-blocker at follow-up were 4.1 ± 2.9 mg for carvedilol and 2.8 ± 1.7 mg for bisoprolol. Patient demographics, concomitant disease, past medical history, and laboratory data on admission including brain natriuretic peptide were not different between the two groups. In the β-blocker group, STEMI was more frequently observed and max creatinine kinase was significantly higher than in the non-β-blocker group. Vital signs at discharge were similar between the two groups. With regard to echocardiography data, LVEF was lower in the β-blocker group than in the non-β-blocker group, although these differences did not reach statistical significance. Other echocardiography data on admission were not different between the two groups. All patients took antiplatelet agents. Statins were prescribed in 98%, and 96% were treated with either an ACE-I or angiotensin II receptor blocker (ARB). During followup, frequency of hospitalization for HF was not different between the two groups (5% in the β-blocker group and 3% in the non-β-blocker group, p = 1.00), and recurrent MI was not observed in either group. 3.2. Changes in vital signs Fig. 2 shows changes in blood pressure (BP) and heart rate (HR) between admission and follow-up in the two groups. Systolic BP increased in both groups (12 mm Hg, 95% CI 8.3 to 16, p b 0.01 in the β-blocker group, and 9.1 mm Hg, 95% CI 2.2 to 16, p = 0.01 in the non-βblocker group, respectively) (Fig. 2A). Diastolic BP also increased in both groups (6.9 mm Hg, 95% CI 3.4 to 10, p b 0.01 in the β-blocker group, and 5.2 mm Hg, 95% CI 0.91 to 9.5, p = 0.02 in the non-βblocker group, respectively) (Fig. 2B). HR decreased in both groups
(− 3.0 bpm, 95% CI − 5.5 to − 0.41, p = 0.02, and − 3.6 bpm, 95% CI −7.1 to −0.07, p = 0.05) (Fig. 2C). 3.3. Changes in echocardiography data Changes in echocardiography data between admission and followup are shown in Fig. 3. LVEF improved in both groups (2.6%, 95% CI 0.87 to 4.3, p b 0.01 in the β-blocker group, and 4.6%, 95% CI 1.9 to 7.4, p b 0.01 in the non-β-blocker group, respectively) (Fig. 3A). Both LVEDVI and LVESVI did not significantly change in the β-blocker group, while both LVEDVI and LVESVI significantly decreased in the non-β-blocker group (LVEDVI: − 4.3 ml/m2, 95% CI − 8.2 to − 0.48, p = 0.03, and LVESVI: − 4.1 ml/m2, 95% CI − 6.3 to − 1.8, p b 0.01) (Fig. 3B, C). There were significant increases of both LVDd and LVDd in the β-blocker group (LVDd: 2.1 mm, 95% CI 1.2 to 2.9, p b 0.01, and LVDs: 2.2 mm, 95% CI 1.3 to 3.2, p b 0.01), while there were no significant changes in both LVDd and LVDs in the non-β-blocker group (Fig. 3D, E). Deceleration time improved in the two groups (35 ms, 95% CI 22 to 48, p b 0.01 in the β-blocker group, and 56 ms, 95% CI 32 to 80, p b 0.01 in the non-β-blocker group, respectively). e′ and E/e′ did not significantly change in the β-blocker group (e′: 0.22 cm/s, 95% CI − 0.24 to 0.68, p = 0.34, and E/e′: − 0.64, 95% CI − 1.6 to 0.31, p = 0.19), while these data significantly improved in the non-β-blocker group (e′: 0.49 cm/s, 95% CI 0.02 to 0.97, p = 0.04, and E/e′: −1.8, 95% CI −2.7 to −0.90, p b 0.01). 4. Discussion The present study showed that the effects of β-blockers on LV remodeling were uncertain in AMI patients with preserved EF who obtained complete coronary revascularization and optimal medical treatments. Although EF improved in the β-blocker group, neither LVEDVI nor LVESVI decreased, and LV diameters increased between admission and follow-up. The beneficial effects of β-blocker on LV remodeling have not been fully elucidated in AMI patients with preserved EF. In the present study, all patients underwent PCI to limit the initial insult of AMI, which is the most effective way to prevent or minimize post-MI cardiac remodeling [11]. These patients also underwent complete coronary revascularization to eliminate the residual ischemic burden. Most patients were treated with an ACE-I or ARB, which are also related to inhibition of LV remodeling. [12,13]. In the β-blocker group, additive beneficial
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Fig. 3. Changes in echocardiography data between admission and follow-up. A. Changes in left ventricular ejection fraction between admission and follow-up. B. Changes in left ventricular end diastolic volume index between admission and follow-up. C. Changes in left ventricular end systolic volume index between admission and follow-up. D. Changes in left ventricular end diastolic diameter between admission and follow-up. E. Changes in left ventricular end systolic diameter between admission and follow-up.
effects of β-blockers were expected to ameliorate LV remodeling. Although EF improved at follow-up in the β-blocker group, neither LVEDVI nor LVESVI improved. LVESV is the most important predictor of prognosis after AMI [14]. Moreover, LV diameters significantly deteriorated rather than improved. In the present study, effects of β-blockers on LV remodeling were uncertain in AMI patients with preserved EF. There could be several reasons for this result. First, in the β-blocker group, STEMI was more frequently observed and max creatinine kinase was significantly higher than in the non-βblocker group. Patients treated with β-blockers could have severe cardiovascular status preventing LV remodeling. However, beneficial effects of β-blockers have been demonstrated in patients with much worse cardiac conditions. As mentioned above, in the CAPRICORN Echo substudy, β-blockers improved LV remodeling in patients with reduced EF [5]. These patients were complicated with more severe ischemic insults compared to the AMI patients with preserved EF. The effects of β-blockers have also been demonstrated in HF patients with very low EF (b 25%) and severe symptoms [15].
Second, the mean dose of β-blockers was relatively lower in the present study than in prior studies. β-Blockers were reported to show dose-related improvement in HF and LVEF [16,17]. On the other hand, in other studies, these relationships were not demonstrated and low dose β-blocker therapy produced important clinical benefit [18,19]. In addition, in the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure (SENIORS) echocardiographic substudy, in which the effect of nebivolol on LV function was observed, neither LVEF, LVEDV, nor LVESV improved in patients with LVEF ≥35% despite a maintenance dose level reached of ≥5 mg in 79.6% of the patients in the study cohort [20]. The relationships between change in HR and LVEF as well as HF prognosis are another aspect of β-blocker therapy currently being investigated. In meta-analysis of patients with systolic HF, a close relationship between a decrease in HR and increase in LVEF was observed [21]. A decrease in HR was also related to improvement in HF prognosis in systolic HF patients [21,22]. In the present study, decrease in HR and improvement of EF were observed in both groups. However, in the β-blocker group, whether
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these favorable changes in HR and LVEF can lead to improvement in HF prognosis is unclear because LVESV, which is the most important predictor of prognosis after AMI [14], did not improve. These results were consisted with the fact that the role of β-blockers in HF with preserved EF has not been fully elucidated [23]. Third, β-blockers have recently been reported to be a risk factor for HF in post-AMI patients. In meta-analysis, Bangalore et al. reported that β-blockers improved mortality in the pre-reperfusion era, while no mortality benefit was observed in the reperfusion era in AMI patients [24]. In the reperfusion era, although β-blockers reduced recurrent MI and angina, the clinical benefit lasted for only 30 days. Moreover, β-blocker therapy increased the rate of HF. Bao et al. reported that in STEMI patients who underwent PCI, β-blockers were not associated with favorable clinical outcomes. In patients with reduced EF, the risk for mortality, MI, and hospitalization for HF were not different among the patients with or without β-blockers. In patients with preserved EF, hospitalization for HF was significantly higher in patients with β-blockers compared to patients without β-blockers after potential confounders were adjusted [25]. The results of the present study and these reports suggest that beneficial effects of β-blockers on HF after AMI are unclear in the reperfusion era, especially in patients with preserved EF. Several potential limitations exist in this study. Class effects of β-blockers were not observed. Both carvedilol and bisoprolol were evaluated at the same time. We do not have information about the timing of titration of β-blockers after discharge. This is a single center observational study and selection bias for the use of β-blockers is inevitable. In conclusion, the effects of β-blockers on LV remodeling were uncertain in AMI patients with preserved EF who obtained complete coronary revascularization and optimal medical treatment. Largescale randomized controlled study is warranted to elucidate the effects of β-blockers on HF in AMI patients with preserved EF in the reperfusion era. Disclosure Kengo Tanabe, remuneration (Abbott Vascular, Terumo, Kaneka, Zeon, Sanofi, Daiichi-Sankyo, Tanabe-Mitsubishi). Acknowledgement of grant support None. References [1] T.D. Fraker Jr., S.D. Fihn, R.J. Gibbons, et al., 2007 chronic angina focused update of the ACC/AHA 2002 guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association task force on practice guidelines writing group to develop the focused update of the 2002 guidelines for the management of patients with chronic stable angina, Circulation 116 (23) (2007) 2762–2772. [2] Task force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC), S. PG, J. SK, et al., 2012 ESC guidelines on acute myocardial infarction (STEMI), Eur. Heart J. 33 (20) (2012) 2569–2619. [3] C.W. Hamm, J.P. Bassand, S. Agewall, et al., ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the task force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC), Eur. Heart J. 32 (23) (2011) 2999–3054.
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