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Meta-Analysis
. 2011 Nov 9;2011(11):CD005184.
doi: 10.1002/14651858.CD005184.pub2.

Creatine and creatine analogues in hypertension and cardiovascular disease

Deborah L Horjus  1 , Inge Oudman, Gert A van Montfrans, Lizzy M Brewster
Affiliations
Meta-Analysis

Creatine and creatine analogues in hypertension and cardiovascular disease

Deborah L Horjus et al. Cochrane Database Syst Rev. .

Abstract

Background: 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.

Objectives: 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.

Search methods: 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.

Selection criteria: 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.

Data collection and analysis: 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.

Main results: 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.

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Conflict of interest statement

Deborah L Horjus, Inge Oudman and Lizzy M Brewster: none known. Gert A van Montfrans has received payments from Merck, Novartis and Daichii Sankyo for lectures and from Daichii Sankyo for development of a course on difficult to treat hypertension. He has also received royalties from Stafleu, Bonn for authoring a book chapter on hypertension and employment income from an outpatient hypertension clinic. He declares that none of these financial activities are related to the subject of this review.

Figures

1
1
Flow chart trial retrieval
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2
Risk of bias summary: review authors judgements about each risk of bias item for each included study
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
4
4
Phosphocreatine versus placebo. Outcome: mortality.
1.1
1.1. Analysis
Comparison 1 Phosphocreatine versus placebo, Outcome 1 Mortality.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Carmenini 1994 {published data only}
    1. Carmenini G. Controlled multicentric clinical study with placebo in patients with dilatative myocardiopathy functional class II‐III N.Y.H.A. treated with oral phosphocreatinine. CUORE RIVISTA DI CARDIOCHIRURGIA E CARDIOLOGIA 1994;11(2):187‐193.
Ferraro 1996 {published data only}
    1. Ferraro S, Codella C, Palumbo F, Desiderio A, Trimigliozzi P, Maddalena G, Chiariello M. Hemodynamic effects of creatine phosphate in patients with congestive heart failure: a double‐blind comparison trial versus placebo. Clin Cardiol 1996 Sep;19(9):699‐703. - PubMed
Gordon 1995 {published data only}
    1. Gordon A, Hultman E, Kaijser L, Kristjansson S, Rolf CJ, Nyquist O, Sylven C. Creatine supplementation in chronic heart failure increases skeletal muscle creatine phosphate and muscle performance. Cardiovasc Res 1995 Sep;30(3):413‐8. - PubMed
Grazioli 1992 {published data only}
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Kuethe 2006 {published data only}
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Maggi 1990 {published data only (unpublished sought but not used)}
    1. Maggi GC, Lomanto B, Mazzola C. Double‐blind multicenter clinical trial on the efficacy of phosphocreatinine vs L‐carnitine and placebo in a group of patients affected by heart disease [Studio clinico in doppio cieco multicentrico sull'efficacia di fosfocreatinina vs L‐carnitina e placebo in un gruppo di cardiopatici]. Acta Toxicol Ther 1990;11(2):173‐184. [EMBASE: 1990393758]
Pedone 1984 {published data only}
    1. Pedone V. An assessment of the activity of creatine phosphate (Neoton) on premature ventricular beats by continuous ECG monitoring in patients with coronary cardiac disease. Clinical trials journal 1984;21(2):91‐99.
Pedone 1984‐2 {published data only}
    1. Pedone V, Corbelli C, Frondini C, Franchi R, Luppi M, Lonardo E, Balboni A, Monetti N, Biase G. Myocardial T1‐201 scintigraphy in the study of the development of acute myocardial infarction. Evaluation of the effects of a drug with metabolic action: creatine phosphate [la scintigrafia miocardica con T1‐201 nello studio dell'evolutione dell'infarto miocardico acuto (AMI): Valutazione degli effetti di un farmaco ad azione metabolica: la creatina fosfato]. La Clinica Terapeutica 1984;111(6):531‐8. - PubMed
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References to studies excluded from this review

Andreev 1992 {published data only}
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Cafiero 1994 {published data only}
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Golikov 1993 {published data only}
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Nedoshivin 1996 {published data only}
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Perepech 1993 {published data only}
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Perepech 2001 {published data only}
    1. Perepech NB, Nedoshivin AO, Nesterova IV. [Neoton and thrombolytic therapy of myocardial infarction] [Neoton i tromboliticheskaia terapiia pri infarkte miokarda]. Ter Arkh 2001;73(9):50‐5. - PubMed
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Stejfa 1993 {published data only}
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Additional references

Brewster 2000
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