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20 August 2015: Clinical Research
Levosimendan Improves Clinical Outcomes of Refractory Heart Failure in Elderly Chinese Patients
Dengqing Zhang ABDE , Yuanqing Yao CE , Jun Qian DE , Jing Huang A
DOI: 10.12659/MSM.893580
Med Sci Monit 2015; 21:2439-2445
Call: +1.631.470.9640
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20 August 2015: Clinical Research
Levosimendan Improves Clinical Outcomes of Refractory Heart Failure in Elderly Chinese Patients
Dengqing Zhang ABDE , Yuanqing Yao CE , Jun Qian DE , Jing Huang A
DOI: 10.12659/MSM.893580
Med Sci Monit 2015; 21:2439-2445
Abstract
BACKGROUND: Levosimendan has been extensively used to treat heart failure (HF) for nearly 10 years, but data on levosimendan used in elderly patients with refractory HF remains limited. This study aimed to investigate the effects of levosimendan on elderly patients with intractable HF.
MATERIAL AND METHODS: A total of 268 patients with HF (over 70 years, New York Heart Association [NYHA] classification III–IV, LVEF ≤40%, plasma NT-proBNP ≥1000 pg/mL) received conventional anti-HF therapies for 2 weeks. Such therapies include the limiting of salt intake, increasing myocardial contractility (without levosimendan), inducing urine, antagonizing aldosterone, antagonizing myocardial remodeling, and, if necessary, using antibiotics. Our study included 42 patients without symptoms whose improvement was re-evaluated and presented in NYHA class III–IV, LVEF ≤40%, plasma NT-proBNP ≥1000.0 pg/mL, and serum creatinine <110.0 µmol/L. These patients were divided into an experimental groups (n=21, treated with levosimendan) and a control group (n=21, continuously given regular treatment as before). After 1 week, 42 patients were assessed for changes in NYHA classification, LVEF, and NT-proBNP.
RESULTS: No severe complications related to levosimendan were noted. Compared with the control group, NYHA classification (I–II: 1 versus 21, III–IV: 20 versus 0, P<0.05) and LVEF (30.62±6.19% versus 45.83±5.06%, P<0.05) were increased, and plasma NT-proBNP was reduced (458.35±193.16 pg/mL versus 2921.52±1395.97 pg/mL, P<0.05) in the experimental group.
CONCLUSIONS: Our study showed levosimendan significantly and safely improved clinical outcomes of refractory heart failure in elderly patients.
Keywords: Anti-Arrhythmia Agents - therapeutic use, Aged, 80 and over, Asian Continental Ancestry Group, Creatinine - blood, Heart Failure - physiopathology, Hydrazones - therapeutic use, Natriuretic Peptide, Brain - blood, Peptide Fragments - blood, Prospective Studies, Pyridazines - therapeutic use, Stroke Volume - drug effects
Background
Congestive heart failure (CHF) is the final endpoint of most cardiovascular diseases and is also a main factor contributing to mortality. In developed countries, 1% to 2% of the adult population is diagnosed with left ventricular dysfunction, but prevalence reaches up to 10% among people over 60-years-old [1]. Mortality in elderly patients is higher than that in younger patients because of several structural and functional changes, such as aortic stiffness and renal impairment [2]. China, the largest developing country in the world, has developed into an aging society because of high morbidity attributed to hypertension, hyperlipidemia, coronary heart disease, and heart dysfunction, which are more common than in developed countries [3].
Molecular biology has been a prominent research focus for the treatment of CHF, which is the key to the prevention or delaying the rapid deterioration of a failing heart [4]. Levosimendan is a new type of Ca2+ sensitizer that can improve myocardial contractility, expand peripheral vessels and the coronary artery, significantly reduce clinical symptoms without increasing myocardial oxygen consumption, and enhance hemodynamics [5]. Levosimendan has been extensively used to treat heart failure (HF) for nearly 10 years. Furthermore, the administration of levosimendan is safe and effective in acute HF [5]. However, data on levosimendan use in elderly patients with refractory HF remains limited.
Given the potential limited data of levosimendan used in elderly patients, in this study we aimed to probe the benefits and safety of levosimendan used only in patients over 70-years-old with intractable HF.
Material and Methods
STUDY POPULATION:
The study followed a prospective, randomized, and open design. HF patients over the age of 70 who had existing symptoms were eligible for this study.
Inclusion Criteria: 1) Symptomatic CHF requiring treatment regardless of previous incidence; 2) No administration of any anti-HF drug within 1–2 weeks; 3) Older than 70 years for both sexes; 4) New York Heart Association classification (NYHA) of grade III to IV, left ventricular ejection fraction (LVEF) of ≤40% by echocardiography and serum N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) was ≥1000 pg/mL by blood testing; 5) Willingness to undergo hospitalization.
Exclusion criteria: 1) Uncorrected primary valve diseases or congenital heart disease; 2) Malignant arrhythmia, such as ventricular tachycardia and ventricular fibrillation; 3) Chronic obstructive pulmonary disease; 4) Electrolyte disturbances and hepatic or renal insufficiency (AST, ALT, total bilirubin, or alkaline phosphatase >2× the upper limit of normal range; serum creatinine >110.0 μmol/L; or serum potassium >5.0 mmol/L); 5) Acute heart dysfunction for the first time; 6) Systolic blood pressure ≥180 mmHg or ≤80 mmHg and/or diastolic blood pressure ≥110 mmHg or ≤50 mmHg, and heart rate ≥180 bpm or ≤50 bpm without installation of pacemaker; 7) Anemia of any etiology (Hb <10.5 g/dL) or any other clinically relevant hematological disease; 8) Evidence of any non-cardiac disease likely to worsen HF significantly or shorten life expectancy; 9) Sensitivity or intolerance to levosimendan and/or some other formulation ingredients; 10) Unlikely to comply with the protocol or unable to understand the nature, scope, and possible consequences of the study after full explanation; and 11) Participation in another trial in the month preceding study entry.
All patients were followed up after a minimum of 4 weeks.
STUDY DESIGN:
All recruited patients underwent regular anti-HF treatments for 2 weeks with salt restriction. Treatments included digitalis and/or milrinone, dobutamine to increase myocardial contractility, frusemide and/or hydrochlorothiazide to induce diuresis, spironolactone to antagonize aldosterone, angiotensin converting enzyme inhibitors (ACE-I) and/or angiotensin II receptor antagonists (ARBs) to antagonize myocardial remodeling and improve prognosis, and, if necessary, antibiotics to treat infection (designated as phase I treatment).
After phase I treatment, all patients were re-evaluated by observing NYHA class, LVEF, plasma NT-proBNP, serum creatinine and beta-blocker (such as metoprolol tablets) were considered for from a small dose if their NYHA class was lower than IV. Forty-two patients who exhibited no improvement in HF symptoms were selected. Their NYHA classifications remained from III to IV, LVEF was ≤40%, NTpro-BNP was ≥1000.0 pg/L, and serum creatinine <110.0 μmol/L. The patients were divided into an experimental group (n=21) and a control group (n=21) following randomized number rules to receive the next phase of treatment (designated as phase II treatment).
MEANS OF USING MEDICINE DURING PHASE II TREATMENT:
The control group, which was similar to phase I treatment, still underwent regular anti-HF treatment with salt restriction, digitalis, dobutamine, frusemide and/or hydrochlorothiazide, spironolactone, and ACE-I and/or ARB. In addition to the aforementioned treatments, the experimental group was intravenously injected with levosimendan (QiLu Medicine Corporation, China; Specifications: 5 mL, 12.5 mg) initially at 12 μg/kg as a primary loading dose (injection time more than 10 min) and then at 0.1 μg/kg/min. After 1 h, the injection speed reached 0.2 μg/kg/min, which was maintained for 23 h [6,7]. In this group, the heart rate and blood pressure were registered at regular intervals. In addition, all patients in this group underwent continuous ECG monitoring.
MEANS OF OBSERVING PARAMETERS DURING THE PHASE II TREATMENT:
After 1 week of phase II treatment, 42 patients were evaluated for the third time according to NYHA classification, LVEF, and NT-proBNP. Some cases had contrasts with their initial values.
STATISTICAL ANALYSIS:
Statistical analysis was performed using SPSS 21.0 software. Measurement data is expressed as mean ±SD. Changes in NYHA classification, LVEF and NT-proBNP before and after phase II treatment in the same group were analyzed using the paired-samples t-test, and the comparisons of different groups were analyzed using the independent-samples t-test. A P value of <0.05 was accepted as statistically significant.
Results
PATIENT CHARACTERISTICS:
A total of 268 patients from the Cardiovascular Ward or from the Outpatient Department of the Second Affiliated Hospital of Chongqing Medical University from May 2013 to November 2014 were included; 146 (53%) were male and 131 (47%) were female. Among all the patients, 127 were cases of coronary heart diseases, 105 were cases of hypertensive heart diseases, and 45 were cases of idiopathic dilated cardiomyopathy. The clinical characteristics of 268 patients are shown in Table 1.
The characteristics of the 42 patients selected from among 268 patients after the phase I treatment are shown in detail in Table 2. Forty-two patients were selected because they exhibited no improvement in HF symptoms after re-evaluation by observing symptoms, NYHA class, LVEF, plasma NT-pro- BNP, and serum creatinine. We found that among these 42 patients, 16 cases were coronary heart disease (9 men, 7 women), 14 cases were hypertensive heart disease (7 men, 7 women), and 12 cases were idiopathic dilated cardiomyopathy (3 men, 8 women). In addition, NYHA classification remained at III to IV, LVEF ≤40%, NTpro-BNP ≥1000.0 pg/L, and serum creatinine <110.0 μmol/L. These patients can be considered to have intractable HF because they had undergone phase I treatment.
Forty-two patients were divided into the experimental group (n=21) and the control group (n=21) following randomized number rules, and the differences in characteristics between these 2 groups had no statistical significance. Comparisons of the clinical characteristics of the control and experimental groups are shown in Table 3.
CLINICAL OUTCOMES:
Compared with treatment before phase II, NYHA classification and LVEF in the experimental group after phase II treatment was significantly increased and NT-proBNP was significantly decreased but only 1 case in the control group showed improvement in NYHA classification (Figures 1–3). Compared with the control group, NYHA classification, LVEF and NT-proBNP were significantly improved in the experimental group. The difference between the experimental and control groups were statistically significant at P<0.05 (Table 4).
COMPLICATIONS RELATED TO LEVOSIMENDAN:
In the experimental group, 21 patients received levosimendan. These patients tolerated levosimendan well and exhibited no complications such as low or high blood pressure, arrhythmia, or aggravation of HF.
Discussion
STUDY LIMITATIONS:
The major limitation of this study is the small population size. The relatively short follow-up of the experimental group is another limitation; thus, we did not determine if levosimendan could improve the long-term prognosis. In addition, the echocardiographic description of the supposed function related to the levosimendan was too simple and we focused only on LVEF, ignoring factors such as diastolic function and the left ventricular dimension.
Conclusions
In this study we observed that levosimendan could significantly and safely improve NYHA classification and LVEF, as well as significantly reduce plasma NT-proBNP in elderly patients with intractable HF. The results suggest that in elderly patients with CHF, especially those patients who had an acute exacerbation of advanced heart failure and did not qualify for conventional anti-CHF treatments, levosimendan would be an option.
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