Effects of levosimendan versus dobutamine on left ventricular diastolic function in patients with cardiogenic shock after primary angioplasty

International Journal of Cardiology 128 (2008) 214 – 217 www.elsevier.com/locate/ijcard

Effects of levosimendan versus dobutamine on left ventricular diastolic function in patients with cardiogenic shock after primary angioplasty Alberto Dominguez-Rodriguez a,⁎, Sima Samimi-Fard a , Martin J. Garcia-Gonzalez a , Pedro Abreu-Gonzalez b a

Department of Cardiology (Coronary Care Unit), Hospital Universitario de Canarias, Tenerife, Spain b Department of Physiology, University of La Laguna, School of Medicine. Tenerife, Spain Received 6 February 2007; received in revised form 21 May 2007; accepted 30 May 2007 Available online 23 July 2007

Abstract Background: Levosimendan is a new calcium sensitizer with positive inotropic properties. In previous studies, it has recently been shown that levosimendan improves the Doppler echocardiographic parameters of the left ventricular (LV) diastolic function in patients with anterior acute myocardial infarction. We sought to evaluate the effects of levosimendan compared to dobutamine on LV diastolic function, using conventional transmitral Doppler, in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) who subsequently developed cardiogenic shock. Methods: We randomized 22 consecutive STEMI patients with cardiogenic shock after primary PCI to levosimendan or dobutamine infusion and we also analyzed the diastolic function using conventional transmitral Doppler flow. Results: Twenty-four hours after the initiation of the drug infusion, patients treated with levosimendan (n = 11) showed a significant reduction of the isovolumetric relaxation time (116 ± 15.2–70.4 ± 10.8 ms; P b.001), and a significant increase of the E/A ratio (0.6 ± 0.3–1.4 ± 0.5; P b.001). In the dobutamine group (n = 11), no statistically significant differences were noted in the echocardiographic Doppler indexes. Conclusion: Levosimendan seems to be effective in improving the Doppler echocardiographic parameters of LV diastolic function in patients with STEMI revascularised by primary PCI who developed cardiogenic shock. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Levosimendan; Dobutamine; ST-segment elevation myocardial infarction; Left ventricular diastolic function; Cardiogenic shock

1. Introduction It has recently been shown that levosimendan, after primary angioplasty in patients with anterior acute myocardial infarction, appears to improve the Doppler echocardiographic parameters of left ventricular (LV) diastolic function [1]. There is few data on the effects of levosimendan versus dobutamine on echocardiographic indexes of LV diastolic function. We sought to assess the effect of levosimendan compared to dobutamine treatment on LV diastolic function in patients ⁎ Corresponding author. Coronary Care Unit, University Hospital of Canarias, Ofra s/n La Cuesta E-38320, Tenerife, Spain. Tel.: +34 922 679030l; fax: +34 922 362716. E-mail address: [email protected] (A. Dominguez-Rodriguez). 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.05.018

with ST-segment elevation myocardial infarction (STEMI) revascularised by primary angioplasty who subsequently developed cardiogenic shock. 2. Methods 2.1. Study patients We assessed 180 patients who were admitted into the Coronary Care Unit of the University Hospital of Canarias with a diagnosis of STEMI [2]. Twenty six (14%) of them developed cardiogenic shock secondary to severe LV systolic dysfunction after primary percutaneous coronary intervention (PCI). Cardiogenic shock was diagnosed according to published criteria [3]. Study design has been described in

A. Dominguez-Rodriguez et al. / International Journal of Cardiology 128 (2008) 214–217 Table 1 Baseline clinical characteristics of the study patients Total population Levosimendan Dobutamine P (n = 22) (n = 11) (n = 11) Age, years Risk factors Smokers (%) Diabetes mellitus (%) Hypertension (%) Dyslipidaemia (%) Multivessel disease (%)

64 ± 14

65 ± 12

63 ± 11

0.68

45 27

50 23

45 30

0.12 0.52

32 54 45

31 64 49

35 45 40

0.29 0.45 0.48

330 ± 60

280 ± 75

0.09

85

64

0.06

0 15

7 29

0.18 0.07

3.55 ± 0.90 1.75 ± 0.6 29 ± 4

3.52 ± 1.05 1.7 ± 0.4 29 ± 2

3.59 ± 0.79 0.86 1.8 ± 0.3 0.51 30 ± 3 0.36

26 ± 5 76 ± 6 85 ± 15 1712 ± 394 28.04 ± 15.30 16.29 ± 9.04

25 ± 4 75 ± 8 85 ± 16 1725 ± 450 28.16 ± 14.47 16.37 ± 8.30

28 ± 6 0.18 77 ± 9 0.58 86 ± 12 0.87 1690 ± 350 0.84 27.81±16.50 0.95 16.16 ± 9.25 0.95

Time delays (min ± SD) Symptom — 1st 310 ± 69 balloon Artery responsible for the STEMI Anterior 73 descending (%) Circumflex (%) 4 Right coronary (%) 23 Hemodynamic data CO (L/min) CI (L/min m2) LV ejection fraction (%) PCWP (mm Hg) MAP (mm Hg) HR (bpm) SVR (dyn s/cm5) SW (g m) SWI (g m/ m2)

Data are expressed as mean ± SD, or percent for categorical variables. STEMI: ST-segment elevation myocardial infarction. CO: Cardiac output. CI: Cardiac index. LV: Left ventricular. PCWP: Pulmonary capillary wedge pressure. MAP: Mean arterial pressure. HR: Heart rate. SVR: Systemic vascular resistance. SW: Stroke work. SWI Stroke work index.

detail elsewhere [4]. Twenty two patients were open-label randomized, in a 1:1 ratio, to receive either levosimendan or dobutamine infusions for 24 h. Levosimendan treatment began with a loading dose of 24 μg kg− 1 over 10 min, followed by a continuous infusion of 0.1 μg kg− 1 min− 1, while dobutamine treatment was initiated with a continuous infusion of 5 μg kg− 1 min− 1 without a loading dose. Infusions were maintained at a constant rate for 24 h, unless dose-limiting events occurred or the patient who suffered either a major cardiovascular event or serious adverse reactions. If any of the following dose-limiting events occurred: symptomatic hypotension; systolic blood pressure b 75 mm Hg; or tachycardia (heart rate N 140 bpm for at least 10 min or increased by N25 bpm) the infusion was interrupted for 30–60 min or until the dose-limiting event had been resolved. The protocol was accepted by the institutional ethical board, and it was performed in accordance to

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institutional guidelines and the Declaration of Helsinki. All patients gave written informed consent before entering the study. 2.2. Study protocol Two investigators of the Coronary Care Unit who had performed Doppler echocardiography for more than 2 years, and had achieved level 3 training in echocardiography performed all Doppler recordings, using a commercially available ultrasound system (Image Point HX, Hewlett Packard, Model: DR5315, USA). Peak transmitral Doppler velocities of early diastolic flow (E) and late diastolic flow (A), deceleration time, and E/A ratio were recorded and analyzed offline. The isovolumetric relaxation time was measured as previously described [5]. The mitral inflow pattern was also recorded during the strain phase of the Valsalva maneuver with real-time 2-dimensional echocardiography to ensure that the placement of the sample volume and angle of interrogation were unchanged with respect to the baseline measurements [6]. Echocardiograms were read in random order with no patient identifiers. Baseline echocardiographic evaluation was performed in all patients on their arrival in the Coronay Care Unit and 24 h after the initiation of levosimendan or dobutamine infusion. The intraobserver and interobserver variabilities for Doppler tracings were assessed using 10 random Doppler recordings. To test the interobserver variability, all Doppler measurements of the randomly selected patients were performed by a second observer who was blinded to the results of the initial echocardiographic examination. As indices of intraobserver and interobserver variability, coefficient variations (mean ± SD) also were calculated. All patients were in sinus rhythm, five consecutive beats were measured and averaged for each Doppler variable. [7]. 2.3. Statistical analyses Categorical variables were expressed as percentages and compared by the chi-square test. Continuous variables are expressed as mean ± SD and they were analyzed by the

Table 2 Additional medication administered in the Coronary Care Unit Coronary Care Unit treatment

Levosimendan (n = 11)

Dobutamine (n = 11)

P

Furosemide Spironolactone Sodium nitroprusside Nitroglycerine Digitalis Lipid lowering agent ACE inhibitor LMW heparin Aspirin Clopidogrel

100 85 75 100 100 100 78 100 100 94

100 90 87 100 100 100 80 100 100 100

1 0.85 0.75 1 1 1 0.90 1 1 1

Data are expressed as percent.

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Student t test. Data were analyzed by the SPSS software package 10.0.1 for PC (Analytical Software, Chicago, IL, USA). A p value b 0.05 was considered statistically significant. 3. Results A total of 22 patients ( mean age 64 ± 14 years; 17 men, 5 women) were admitted into the Coronary Care Unit with STEMI and they developed cardiogenic shock within the following 24 h of a successful primary PCI procedure. Eleven patients were assigned to levosimendan and eleven to dobutamine treatment. Clinical characteristics of the study population are summarized in Table 1. The 2 study groups were well balanced with respect to additional medication administered in the Coronary Care Unit, with stable doses during the study (Table 2). None of the patients developed multiple organ failure. The use of intra-aortic counterpulsation balloons was only used in one case in the levosimendan treatment group. Baseline LV ejection fraction was similar among the patients and showed no statistically significant differences between the groups in the acute phase of STEMI (p = 0.36). LV ejection fraction, measured at 24 h after initiated the levosimendan or dobutamine infusion, was significantly better in the levosimendan-treated group (55 ± 8% versus 45 ± 6%, p b 0.05). All baseline Doppler parameters were comparable between the two groups (Table 3). Twenty-four hours after the initiation of the drug infusion, patients treated with levosimendan had a significant reduction of the isovolumetric relaxation time (116 ± 15.2–70.4 ± 10.8 ms; P b.001), and a significant increase of the E/A ratio (0.6 ± 0.3–1.4 ± 0.5; P b.001). In the dobutamine group, no statistically significant differences were noted in the echocardiographic Doppler indexes. For peak mitral E and mitral A wave velocity, the E/A ratio, the deceleration time of the mitral E wave velocity and isovolumetric relaxation time, the intraobserver variability was 0.04 ± 0.02 m/s, 0.03 ± 0.03 m/s, 0.02 ± 0.02, 5.5 ± 1.4 ms, and 8.5 ± 2.6 ms, respectively. For the same measurements, interobserver variability was 0.04 ± 0.02 m/s, 0.02 ± 0.01, 0.02 ± 0.03, 5.9 ± 3.1 ms, and 7.0 ± 5.4 ms, respectively.

Table 3 Doppler echocardiographic data at baseline and 24 h after of initiated the drug infusion Levosimendan (n = 11)

Dobutamine (n = 11)

Baseline

At 24 h

Baseline

At 24 h

1.4 ± 0.5 ⁎ 198 ± 16 70.4 ± 10.8 ⁎

0.7 ± 0.2 200.24 ± 11.8 114.7 ± 9.4

0.9 ± 0.3 188 ± 13.4 102.8 ± 12.4

Conventional Doppler E/A ratio 0.6 ± 0.3 DT, ms 212.14 ± 15.8 IVRT, ms 116 ± 15.2

Data are expressed as mean ± SD. A: late diastolic flow. E: early diastolic flow. IVRT: isovolumetric relaxation time. DT: deceleration time. ⁎ Significant difference (P b.001) between baseline and 24-hour values.

4. Discussion In this randomized and open-label trial, we showed for the first time that the novel inodilator agent levosimendan compared to dobutamine cause a significant reduction of the isovolumetric relaxation time, and a significant increase of the E/A ratio in patients with STEMI revascularised by primary PCI who developed cardiogenic shock. In previous studies from our group, we have found that levosimendan might be beneficial in cardiogenic shock, especially when it complicates acute myocardial infarction [4,8,9]. We observed that, in this type of patient, levosimendan improved cardiac reserve pumping and it increased both cardiac index and cardiac power [10] significantly more than dobutamine at the studied doses. The presence of diastolic filling abnormalities may lead inadequate cardiac output even though the ejection fraction is normal or near normal [11]. In patients with low-output state, treatments are often aimed at improving LV contractile performance, but they may conflict with appropriate therapy for diastolic abnormalities. In light of the impaired relaxation that often accompanies systolic dysfunction, general enhancement of calcium sensitivity might have negative effects. Increased sensitivity to calcium during diastole would further hamper diastolic relaxation time, worsening diastolic dysfunction [12]. Levosimendan acts through direct binding with troponinC increasing its affinity for calcium in a calcium-dependent manner [13]. A lack of sensitization under low prevailing calcium concentrations during diastole might be of critical importance to prevent a worsening of diastolic dysfunction [13]. A prolonged relaxation time has been shown to further impair diastolic function when using other calcium sensitizers [14]. Conversely, the effect of levosimendan on diastolic properties and cardiac relaxation is incompletely understood. These findings are in keeping with prior data published by other authors, suggesting that the levosimendan improved both systolic and diastolic function [15,16]. In a study by De Luca et al. [1], levosimendan after primary PCI in patients with anterior acute myocardial infarction, improved the Doppler echocardiographic parameters of LV diastolic function. Conversely, in our study we evaluated patients with cardiogenic shock in the setting of an acute myocardial infarction. The classic paradigm of cardiogenic shock has traditionally been viewed as simply a mechanical problem: an acute reduction in myocardial contractility leads to reduced stroke volume and cardiac output, which leads to hypotension and systemic hypoperfusion [17]. Recent data suggest that this paradigm should be expanded [18]. Studies have revealed a pivotal role for a systemic inflammatory response that includes the release of inflammatory mediators, the expression of inducible nitric oxide, and an inappropriate peripheral circulatory response [18]. Likewise, levosimendan has recently shown antiinflammatory and anti-apoptotic action by means of promoting gene transcription, cell growth, and mitochondrial volume regulation, thus preventing mitochondrial structure and

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function disruption and facilitating efficient energy transfer between mitochondrial and myofibrillar ATPases [8,19,20]. Furthermore, it has recently been demonstrated that levosimendan induced improvement of LV diastolic function accompanied by beneficial neurohormonal modulation [21]. Thus, levosimendan appears to intervene beneficially in the systemic inflammatory response, myocardial injury, and intracellular calcium handling abnormalities, improving systolic and diastolic function in patients with severe heart failure [22]. These actions are essential for the improvement of left ventricular function after cardiovascular injury. Despite the novelty and importance of our findings, our study has limitations. Analysis of the mitral inflow velocity curve has provided useful information for determination of filling pressures and prediction of prognosis in patients with LV systolic dysfunction, especially when ejection fraction is smaller than 50% [23], as in our study population. Unfortunately, mitral flow is dependent on multiple interrelated factors, including the rate and extent of ventricular relaxation, atrial and ventricular compliance, mitral valve inertness, and left atrial pressure, which may have confounding effects on the mitral inflow [24]. On the other hand, pulmonary venous flow patterns were not assessed because of technical difficulty in the context of haemodynamic unstable patients. The available ultrasound system in our Coronary Care Unit has not Doppler tissue capabilities, therefore, Doppler tissue parameters were not obtained in our study. In conclusion, our study shows that levosimendan compared to dobutamine, seems to improve conventional Doppler parameters of LV diastolic function in STEMI patients who developed cardiogenic shock following primary PCI. Acknowledgements The authors wish to express their gratitude to Ines AbreuAfonso for the linguistic aids in preparing the manuscript. References [1] De Luca L, Sardella G, Proietti P, et al. Effects of levosimendan on left ventricular diastolic function after primary angioplasty for acute anterior myocardial infarction: a Doppler echocardiographic study. J Am Soc Echocardiogr 2006;19:172–7. [2] Myocardial infarction redefined — a consensus of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. Eur Heart J 2000;21:1502–13. [3] Alexander RW, Pratt CM, Ryan TJ, Roberts R. Diagnosis and management of patients with acute myocardial infarction. In: Fuster V, Alexander RW, O’Rourke RA, editors. Hurst's the heart. 10th ed. New York: McGraw-Hill Company, Inc.; 2001. p. 1275–359. [4] Garcia-Gonzalez MJ, Dominguez-Rodriguez A, Ferrer-Hita JJ, AbreuGonzalez P, Bethencourt-Muñoz M. Cardiogenic shock after primary percutaneous coronary intervention: Effects of levosimendan compared with dobutamine on haemodynamics. Eur J Heart Fail 2006;8:723–8. [5] Mulvagh S, Quinones MA, Kleiman NS, Cheirif J, Zoghbi WA. Estimation of left ventricular end diastolic pressure from Doppler transmitral flow velocity in cardiac patients independent of systolic performance. J Am Coll Cardiol 1992;20:112–9.

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