Horjus Deborah L, Oudman Inge, van Montfrans Gert A, Brewster Lizzy M
1Department of Internal Medicine, Division of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam,Netherlands.
Cochrane Database Syst Rev. 2011 Nov 9;2011(11):CD005184. doi: 10.1002/14651858.CD005184.pub2.
The creatine kinase system, the central regulatory system of cellular energy metabolism, provides ATP in situ at ATP-ases involved in ion transport and muscle contraction. Furthermore, the enzyme system provides relative protection from tissue ischaemia and acidosis. The system could therefore be a target for pharmacologic intervention.
To systematically evaluate evidence regarding the effectiveness of interventions directly targeting the creatine kinase system as compared to placebo control in adult patients with essential hypertension or cardiovascular disease.
Electronic databases searched: Medline (1950 - Feb 2011), Embase (up to Feb 2011), the Cochrane Controlled Trials Register (issue 3, Aug 2009), Latin-American/Caribbean databank Lilacs; references from textbooks and reviews; contact with experts and pharmaceutical companies; and searching the Internet. There was no language restriction.
Randomized controlled trials comparing creatine, creatine phosphate, or cyclocreatine (any route, dose or duration of treatment) with placebo; in adult patients with essential hypertension, heart failure, or myocardial infarction. We did not include papers on the short-term use of creatine during cardiac surgery.
The outcomes assessed were death, total myocardial infarction (fatal or non-fatal), hospitalizations for congestive heart failure, change in ejection fraction, and changes in diastolic and systolic blood pressure in mm Hg or as percent change.
Full reports or abstracts from 1164 papers were reviewed, yielding 11 trials considering treatment with creatine or creatine analogues in 1474 patients with heart failure, ischemic heart disease or myocardial infarction. No trial in patients with hypertension was identified. Eleven trials (1474 patients, 35 years or older) comparing add-on therapy of the creatine-based drug on standard treatment to placebo control in patients with heart failure (6 trials in 1226 / 1474 patients ), or acute myocardial infarction (4 trials in 220 / 1474 patients) or 1 in ischemic heart disease (28 / 1474 patients) were identified. The drugs used were either creatine, creatine phosphate (orally, intravenously, or intramuscular) or phosphocreatinine. In the trials considering heart failure all three different compounds were studied; creatine orally (Gordon 1995, Kuethe 2006), creatine phosphate via intravenous infusion (Ferraro 1996, Grazioli 1992), and phosphocreatinine orally (Carmenini 1994, Maggi 1990). In contrast, the acute myocardial infarction trials studied intravenous creatine phosphate only. In the ischemic heart disease trial (Pedone 1984) creatine phosphate was given twice daily through an intramuscular injection to outpatients and through an intravenous infusion to inpatients. The duration of the study intervention was shorter for the acute patients, from a two hour intravenous infusion of creatine phosphate in acute myocardial infarction (Ruda 1988, Samarenko 1987), to six months in patients with heart failure on oral phosphocreatinine therapy (Carmenini 1994). In the acute myocardial infarction patients the follow-up period varied from the acute treatment period (Ruda 1988) to 28 days after start of the symptoms (Samarenko 1987) or end of the hospitalization period (Zochowski 1994). In the other trials there was no follow-up after discontinuation of treatment, except for Gordon 1995 which followed the patients until four days after stopping the intervention.Only two out of four trials in patients with acute myocardial infarction reported mortality outcomes, with no significant effect of creatine or creatine analogues (RR 0.73, CI: 0.22 - 2.45). In addition, there was no significance on the progression of myocardial infarction or improvement on ejection fraction. The main effect of the interventions seems to be on improvement of dysrhythmia.
AUTHORS' CONCLUSIONS: This review found inconclusive evidence to decide on the use of creatine analogues in clinical practice. In particular, it is not clear whether there is an effect on mortality, progression of myocardial infarction and ejection fraction, while there is some evidence that dysrhythmia and dyspnoea might improve. However, it is not clear which analogue, dose, route of administration, and duration of therapy is most effective. Moreover, given the small sample size of the discussed trials and the heterogeneity of the population included in these reports, larger clinical studies are needed to confirm these observations.
肌酸激酶系统是细胞能量代谢的核心调节系统，可在参与离子转运和肌肉收缩的ATP酶处原位提供ATP。此外，该酶系统可对组织缺血和酸中毒起到一定的保护作用。因此，该系统可能成为药物干预的靶点。
系统评价与安慰剂对照相比，直接针对肌酸激酶系统进行干预对成年原发性高血压或心血管疾病患者有效性的证据。
检索电子数据库：Medline（1950年至2011年2月）、Embase（截至2011年2月）、Cochrane对照试验注册库（2009年8月第3期）、拉丁美洲/加勒比数据库Lilacs；教科书和综述中的参考文献；与专家及制药公司联系；以及在互联网上搜索。无语言限制。
比较肌酸、磷酸肌酸或环肌酸（任何给药途径、剂量或治疗持续时间）与安慰剂的随机对照试验；受试者为成年原发性高血压、心力衰竭或心肌梗死患者。我们未纳入有关心脏手术期间短期使用肌酸的论文。
评估的结局包括死亡、总的心肌梗死（致命或非致命）、因充血性心力衰竭住院、射血分数变化以及舒张压和收缩压以毫米汞柱为单位的变化或百分比变化。
共查阅了1164篇论文的完整报告或摘要，得到11项试验，涉及1474例心力衰竭、缺血性心脏病或心肌梗死患者接受肌酸或肌酸类似物治疗。未找到高血压患者的试验。确定了11项试验（1474例患者，年龄35岁及以上），比较在心力衰竭患者（1226/1474例患者中的6项试验）、急性心肌梗死患者（220/1474例患者中的4项试验）或缺血性心脏病患者（28/1474例患者中的1项试验）中，在标准治疗基础上加用基于肌酸的药物与安慰剂对照的附加治疗。使用的药物为肌酸、磷酸肌酸（口服、静脉注射或肌肉注射）或磷酸肌酸酐。在考虑心力衰竭的试验中，研究了所有三种不同的化合物；口服肌酸（Gordon 1995年、Kuethe 2006年）、静脉输注磷酸肌酸（Ferraro 1996年、Grazioli 1992年）以及口服磷酸肌酸酐（Carmenini 1994年、Maggi 1990年）。相比之下，急性心肌梗死试验仅研究了静脉注射磷酸肌酸。在缺血性心脏病试验（Pedone 1984年）中，门诊患者通过肌肉注射、住院患者通过静脉输注给予磷酸肌酸，每日两次。急性患者的研究干预持续时间较短，从急性心肌梗死中两小时静脉输注磷酸肌酸（Ruda 1988年、Samarenko 1987年）到口服磷酸肌酸酐治疗的心力衰竭患者的六个月（Carmenini 1994年）。在急性心肌梗死患者中，随访期从急性治疗期（Ruda 1988年）到症状开始后28天（Samarenko 1987年）或住院期结束（Zochowski 1994年）不等。在其他试验中，除Gordon 1995年在干预停止后对患者随访至四天外，治疗停止后无随访。急性心肌梗死患者的四项试验中只有两项报告了死亡率结局，肌酸或肌酸类似物无显著影响（RR 0.73，CI：0.22 - 2.45）。此外，在心肌梗死进展或射血分数改善方面也无显著性差异。干预的主要作用似乎是改善心律失常。
本综述发现，关于在临床实践中使用肌酸类似物的证据尚无定论。特别是，目前尚不清楚其对死亡率、心肌梗死进展和射血分数是否有影响，而有一些证据表明心律失常和呼吸困难可能有所改善。然而，尚不清楚哪种类似物、剂量、给药途径和治疗持续时间最为有效。此外，鉴于所讨论试验的样本量较小以及这些报告中纳入人群的异质性，需要开展更大规模的临床研究来证实这些观察结果。
