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- Vincenzo De Santis, Domenico Vitale, Fabio Pellegrini, Luigi Tritapepe (7 April 2009)
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Reply to levosimendan's effect on platelet function
- Vincenzo De Santis, Domenico Vitale, Luigi Tritapepe, (7 March 2009)
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LEVOSIMENDAN’S EFFECT ON PLATELET FUNCTION
- Kürşad KAPTAN, Cengiz BEYAN, Ahmet IFRAN (2 March 2009)
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Clinical outcome benefits of pre-treatment with levosimendan in surgical myocardial revascularizatio
- Judith M.D. van den Brule, Cornelia Hoedemaekers and Peter Pickkers (25 February 2009)
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Vincenzo De Santis "Sapienza" University of Rome, Domenico Vitale, Fabio Pellegrini, Luigi Tritapepe
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We thank Pickkers and colleagues for their insightful queries about our article. To address the first question raised, baseline ejection fraction (EF) was dichotomized as ≤35% vs. >35%. The patients in the treatment group with an EF≤35% showed a significant reduction in ICU length of stay compared with the same subgroup of the controls [26.2 (4.8) vs. 37.1 (11.9), Mann-Whitney U-test p=0.0184]. As to the second point, Table 1 reports frequencies and percentage in treatment and control groups for ICU length of stay categorized in three classes. The overall association was assessed with Fisher's exact test (p=0.0051). In particular, the proportion of patients with ICU length of stay<24 hours was 48.1% in levosimendan and 28.0% in the control group. To assess how time on ventilator and inotropes mediate levosimendan effect on ICU length of stay, unadjusted and adjusted linear regression models for the log-transformed endpoint were used. Back-transformed marginal means for the unadjusted model were 23.9 in the levosimendan group and 30.3 in controls, p=0.0007. After adjustment for time on ventilator (in tertiles) and received inotropes, marginal means did not change (24.4 vs. 29.7, p=0.0058). Similar results were obtained when a logistic model instead of a linear model was used, with a cutoff for ICU stay of <24 hours or <36 hours (table 2). attachment link Conflict of Interest:None declared |
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Vincenzo De Santis , Domenico Vitale, Luigi Tritapepe,
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Letter We thank Kaptan and colleagues for their interest in our work. Their study with an in vitro model showed that levosimendan had a significant inhibitory effect on platelets function in healthy volunteers. In our patients population no clinically significant differences in terms of blood loss and transfusion requirements were detected. Even in the SURVIVE study, which is the largest multicenter randomized trial in the setting of acute decompensated heart failure, the authors did not find any difference in terms of anemia. On the basis of the current evidence the in vitro levosimendan effect on platelet function would not appear to translate into a clinically relevant impact on bleeding. References 1. Kaptan K, Erinç K, Ifran A, et al. Levosimendan has an inhibitory effect on platelet function. Am J Hematol 2008; 83: 46-49 2. Tritapepe L, De Santis V, Vitale D, et al. Levosimendan pre- treatment improves outcomes in patients undergoing coronary artery bypass graft surgery. Br J Anaesth 2009; 102: 198-204 3. Mebazaa A, Nieminen MS, Packer M, et al. SURVIVE Investigators Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. JAMA 2007; 297: 1883 – 91 Conflict of Interest:None declared |
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Kürşad KAPTAN , Cengiz BEYAN, Ahmet IFRAN
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We have read with interest Tritapepe and colleagues’ recently published article related to short pre-treatment with levosimendan in patients undergoing myocardial revascularization.1 Authors aimed to see whether pharmacological pre-treatment with levosimendan reduces intensive care unit (ICU) length of stay in patients undergoing elective myocardial revascularisation under cardiopulmonary bypass. The study showed that pre- treatment with levosimendan resulted in a reduction of tracheal intubation time, decreased requirement for inotropic support and a shorter duration of ICU stay. In this study, no haematological side effect as bleeding problem related to levosimendan was reported. However, the effect of levosimendan on platelet aggregation was investigated.2 This study reported that levosimendan inhibited aggregation of platelets induced by ADP and collagen significantly, although the mechanism of action of the agent is not known. The study results displayed that there was a relationship between levosimendan concentration and inhibition of platelet aggregation. The clinical significance of the diminishing effect of levosimendan on the responsiveness of normal platelets to aggregatory agents is not known. However, it is possible that other medications used in patients undergoing myocardial revascularization may have antiplatelet effects and levosimendan may also aggravate this effect. For example, it is reported in baseline characteristics of patients by Tritapepe and colleagues’ study that platelet inhibitory therapy was used by 51% of levosimendan group. Other possible important point, in patients with platelet function defects or thrombocytopenia, levosimendan may cause clinically problematic situation. However, in Tritapepe and colleagues’ study, levosimendan (24 µg kg-1) was used only before the initiation cardiopulmonary bypass. Although possible adverse effect of levosimendan on platelet may be regarded due to only one dose administration of levosimendan, it is known that the active metabolite of levosimendan has a long half-life (~80 h) and circulates for about 2 weeks.3 Because of long half-life of levosimendan, patient may be exposed to drug until discharge from hospital after surgery. On the other hand, it is possible to think that antiaggregatory effect of levosimendan may have no clinical significance, because of no reported bleeding problems in levosimendan- treated patients as in Tritapepe and colleagues’ study. However, the potential effect of levosimendan should be borne in mind while administrating it especially in patients receiving concomitant medications that have possible effects on platelet function. Kürşad KAPTAN, MD Cengiz BEYAN, MD Ahmet IFRAN, MD Hematology Department School of Medicine Gülhane Military Medical Academy Etlik, Ankara, Turkey E-mail: mkkaptan@hotmail.com REFERENCES 1) Tritapepe L, De Santis V, Vitale D, et al. Levosimendan pre-treatment improves outcomes in patients undergoing coronary artery bypass graft surgery. Br J Anaesth 2009; 102(2): 198-204 2) Kaptan K, Erinç K, Ifran A, et al. Levosimendan has an inhibitory effect on platelet function. Am J Hematol 2008; 83: 46-49 3) Antila S, Pesonen U, Lehtonen L, et al. Pharmacokinetics of levosimendan and its active metabolite OR-1896 in rapid and slow acetylators. Eur J Pharm Sci 2004; 23: 213–222 Conflict of Interest:None declared |
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Judith M.D. van den Brule Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, The Netherlands, Cornelia Hoedemaekers and Peter Pickkers
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Dear editor, Recently Tritapepe et al. [1] reported that pre-treatment with levosimendan in patients undergoing elective surgical myocardial revascularization results in less myocardial injury, a reduction in tracheal intubation time, less requirement for inotropic support, and a shorter ICU length of stay. This is the first study that demonstrates clinical outcome benefit with the use of levosimendan in such a patient population. Pre-treatment with levosimendan has beneficial effects on myocardial function of patients with an impaired ejection fraction [2] as well as of patients with a normal ejection fraction [3]. Following physiological principles, clinical outcome benefit is likely to be more relevant in patients with impaired cardiac function, but this has not been demonstrated in humans yet. In the study of Tritapepe et al., 95% of the studied patients had a baseline ejection fraction between approximately 20 and 60%. This considerable variation would make it possible to correlate baseline ejection fraction with the beneficial effects of levosimendan. This additional analysis could possibly demonstrate that patients with an impaired ejection fraction treated with levosimendan need less inotropic support resulting in a shorter ICU stay. As these effects may not be of clinical relevance in patients with a better ejection fraction, a patient group more likely to benefit of levosimendan treatment can be identified. Second, the authors report that length of ICU length of stay was 12 hours less on average in the levosimendan-treated group. As patients are not routinely discharged during evening or night hours, and to further emphasize the clinical relevance of this observation, it would be of interest to show the proportion of patients that had an ICU length of stay of 1, 2 or longer than 2 days. Moreover, in view of the differences between the levosimendan and placebo group in time on ventilator and number of patients on inotropes, in our opinion it would be of relevance to show how these end points interact with each other and mediate ICU length of stay. References: 1. Tritapepe L., De Santis V., Vitale D., Guarracino F., Pellegrini F., Pietropaoli P. and Singer M. Levosimendan pre-treatment improves outcomes in patients undergoing coronay artery bypass graft surgery. Br J Anaesth 2009; 102: 198-204. 2. De Hert S.G., Lorsomradee S., vanden Eede H., Cromheecke S. and Van der Linden P.J. A randomized trial evaluating different modalities of levosimendan administration in cardiac surgery patients with myocardial dysfunction. J Cardiothorac Vasc Anesth 2008; 22: 699-705. 3. Barisin S., Husedzinovic I., Sonicki Z., Bradic N., Barisin A. and Tonkovic D. Levosimendan in off-pump coronary artery bypass: a four-times masked controlled study. J Cardiovasc Pharmacol 2004; 44: 703-8. Correspondence: p.pickkers@ic.umcn.nl Conflict of Interest:None declared |
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