Hemodynamic effects of creatine phosphate in patients with congestive heart failure: a double-blind comparison trial versus placebo. Creatine supplementation improves muscle strength in patients with congestive heart failure. Effect of sodium nitroprusside on mortality in acute myocardial infarction. Creatine supplementation in chronic heart failure increases skeletal muscle creatine phosphate and muscle performance. Effect of rosuvastatin pretreatment on myocardial damage after coronary surgery: a randomized trial. A randomized sequential trial of creatine in amyotrophic lateral sclerosis. A randomized study of intravenous magnesium in acute myocardial infarction treated with direct coronary angioplasty. Beneficial effects of diltiazem during myocardial reperfusion: a randomized trial in acute myocardial infarction. CINRG randomized controlled trial of creatine and glutamine in Duchenne muscular dystrophy.
The use of metabolic drugs effective in addition to conventional therapy represents a significant challenge in patients with left ventricular dysfunction.
                The aim of this double-blind, placebo-controlled study was to investigate the hemodynamic effects of acute intravenous (i.v.) administration of creatine phosphate (CP) and of short-term treatment in patients with congestive heart failure (CHF) from ischemic heart disease (IHD) or dilated cardiomyopathy in addition to conventional therapy.
                We compared the hemodynamic effects of exogenous creatine phosphate (CP) and placebo in a double-blind, crossover design study in 13 hospitalized patients (12 men, 1 woman, mean age 52 +/- 8 years) with CHF. All patients were in New York Heart Association (NYHA) class II-III and received conventional pharmacologic therapy for CHF; this was not changed during the study period. The study design consisted of two treatment periods (CP or placebo and placebo or CP, respectively) of 4 days each, separated by a 2-day washout interval. The intravenous infusion consisted of 6 g CP or placebo (acute treatment) or 6 g CP or placebo daily for 4 days (short-term treatment) diluted in 50 ml of NaCl 0.9%; infusion duration was about 10 min. Mono-bidimensional echocardiographic examination (Hewlett Packard Sonos 1000, with a 2.5 MHz transducer) was performed at baseline, after acute infusion, and 12 h after the end of short-term treatment. Data were analyzed by ANOVA and Student's t-test for paired data; the results obtained after acute and short-term therapy were compared with the baseline values.
                After placebo therapy, no significant change was observed. The results after treatment with CP showed a significant reduction of end-systolic diameter [baseline: 4.5 +/- 0.6; acute: 4.2 +/- 0.5, (p < 0.001); short-term 4.3 +/- 0.6 cm, (p < 0.05)] and systemic vascular resistance (baseline: 1064.9 +/- 483.7; acute: 947.5 +/- 390.2 (p < 0.05); short-term: 950.7 +/- 394.3 dyne-s-cm-5 (p < 0.05); moreover, a significant increase of percent ejection fraction [baseline: 48 +/- 12%; acute 53 +/- 12% (p < 0.01); short-term 52 +/- 11% (p < 0.01)], and of percent fractional shortening [baseline: 25 +/- 7; acute 28 +/- 8 (p < 0.05); short-term 28 +/- 7% (p < 0.05)] was observed.
                CP was shown to improve cardiac function, even in the presence of a conventional CHF pharmacologic therapy. Both, cardiac and skeletal muscle creatine levels are depressed in patients with congestive heart failure (CHF). Oral supplementation of creatine (Cr) could increase physical performance in healthy volunteers. We therefore hypothesized that oral creatine supplementation improves skeletal muscle strength, quality of live and symptom-limited performance in patients with CHF.
                In a double-blind, placebo-controlled and crossover-designed study, 20 patients suffering from congestive heart failure more than 6 months and a peak oxygen uptake (peak VO2) below 20 ml/min/kg received 4 x 5 g Cr daily vs. placebo for 6 weeks and were crossed over for the following 6 weeks. Peak VO2, VO2 at the anaerobic threshold (VO2AT), ejection fraction (EF), distance in 6-minute-walk-test (6 min W), and muscle strength (Modified Sphygmomanometer (MS)) were determined at baseline, after 6, and after 12 weeks. Dyspnoea after 6-minute-walk-test was measured using the Borg Scale. Quality of live was assessed with the Minnesota Living with Heart Failure Questionnaire (MLHFQ).
                13 of 20 Patients finished the study. After 6 weeks of creatine supplementation there was a significant increase in body weight and muscle strength compared to baseline and placebo (p < 0.05). However, there was no significant change in peak VO2, VO2AT, walking distance, quality of life assessment and EF.
                Short-term creatine supplementation inaddition to standard medication in patients with CHF leads to an increase in body weight and an improvement of muscle strength. This effect is restricted to the time of supplementation. We gave sodium nitroprusside by intravenous infusion to 163 randomly selected patients during the first 24 hours after hospitalization for typical acute myocardial infarction, and we studied its effects on mortality at one week, on the incidence of cardiogenic shock, on clinical signs of left ventricular failure, and on peak levels of creatine kinase isoenzyme MB. A control group of 165 patients received standard medical treatment and infusion of 5 per cent glucose. The end point of the study was a significant reduction in mortality in the nitroprusside group; this was reached when five deaths had occurred in this group, as compared with 18 among the controls (P less than 0.05). The incidence of cardiogenic shock, clinical signs of left-heart failure, and mean peak levels of creatine kinase isoenzyme MB were all reduced (P less than 0.05). The results indicate that infusion of nitroprusside in the early phase of acute infarction limits complications, possibly by reducing infarct size. The drug was particularly effective in anterior-wall infarction. Cardiac creatine levels are depressed in chronic heart failure. Oral supplementation of creatine to healthy volunteers has been shown to increase physical performance.
                To evaluate the effects of creatine supplementation on ejection fraction, symptom-limited physical endurance and skeletal muscle strength in patients with chronic heart failure.
                With a double-blind, placebo-controlled design 17 patients (age 43-70 years, ejection fraction < 40) were supplemented with creatine 20 g daily for 10 days. Before and on the last day of supplementation ejection fraction was determined by radionuclide angiography as was symptom-limited 1-legged knee extensor and 2-legged exercise performance on the cycle ergometer. Muscle strength as unilateral concentric knee extensor performance (peak torque, Nm at 180 degrees/s) was also evaluated. Skeletal muscle biopsies were taken for the determination of energy-rich phosphagens.
                Ejection fraction at rest and at work did not change. Performance before creatine supplementation did not differ between placebo and creatine groups. While no change was seen in the placebo group compared to baseline, creatine supplementation increased skeletal muscle total creatine and creatine phosphate by 17 +/- 4% (P < 0.05) and 12 +/- 4% (P < 0.05), respectively. Increments were seen only in patients with < 140 mmol total creatine/kg d.w. (P < 0.05). One-legged performance (21%, P < 0.05), 2-legged performance (10%, P < 0.05), and peak torque, Nm (5%, P < 0.05) increased. Both peak torque and 1-legged performance increased linearly with increased skeletal muscle phosphocreatine (P < 0.05). The increments in 1-legged, 2-legged and peak torque were significant compared to the placebo group, (P < 0.05).
                One week of creatine supplementation to patients with chronic heart failure did not increase ejection fraction but increased skeletal muscle energy-rich phosphagens and performance as regards both strength and endurance. This new therapeutic approach merits further attention. Myocardial disease without evidence of myocardial infarction is a frequent complication after cardiac surgery during cardiopulmonary bypass. Statins might be protective, but their efficacy has not been established in randomized trials.
                Two hundred patients undergoing coronary surgery were enrolled. They were randomized to rosuvastatin (20 mg/d, n = 100) or placebo (n = 100) starting 1 week before the operation. Troponin I, myoglobin, creatine kinase-MB mass, and high-sensitivity C-reactive protein were used as markers of myocardial injury, and their values were determined at baseline and at regular intervals after the operation. Electrocardiography and echocardiography were performed before and after the operation.
                Myocardial disease was diagnosed when troponin I, myoglobin, and creatine kinase-MB mass values were above the upper normal limit without evidence of electrocardiographic changes, echocardiographic changes, or both. The percentages of marker level increase indicative of myocardial disease were determined in the placebo versus statin groups and were as follows: troponin I, 35% versus 65% (P < .0001); myoglobin, 39% versus 72% (P < .0001); creatine kinase-MB mass, 22% versus 40% (P = .0002). Peak postoperative values of troponin I (0.16 +/- 0.15 vs 0.32 +/- 0.26 ng/mL, P = .0008), myoglobin (72.25 +/- 25 vs 98.31 +/- 31 ng/mL, P < .0001), and creatine kinase-MB mass (3.9 +/- 3.3 vs 9.3 +/- 8.1 ng/mL, P < .0001) were significantly higher in the placebo group. High-sensitivity C-reactive protein values were increased in 58% of pretreated versus 88% of the control patients (15.4 +/- 2.5 vs 17.2 +/- 3.4 mg/L, P < .0001). In high-risk patients myocardial disease was observed more frequently but significantly less in statin-pretreated patients.
                Statin pretreatment reduces myocardial damage after coronary surgery and could improve both short- and long-term results. Amyotrophic lateral sclerosis (ALS) is a fatal disease with no cure. In a transgenic mouse model of ALS, creatine monohydrate showed a promising increase in survival. We performed a double-blind, placebo-controlled, sequential clinical trial to assess the effect of creatine monohydrate on survival and disease progression in patients with ALS. Between June 2000 and December 2001, 175 patients with probable, probable-laboratory supported, or definite ALS were randomly assigned to receive either creatine monohydrate or placebo 10 gm daily. A sequential trial design was used with death, persistent assisted ventilation, or tracheostomy as primary end points. Secondary outcome measurements were rate of decline of isometric arm muscle strength, forced vital capacity, functional status, and quality of life. The trial was stopped when the null hypothesis of indifference was accepted. Creatine did not affect survival (cumulative survival probability of 0.70 in the creatine group vs 0.68 in the placebo group at 12 months, and 0.52 in the creatine group vs 0.47 in the placebo group at 16 months), or the rate of decline of functional measurements. Creatine intake did not cause important adverse reactions. This placebo-controlled trial did not find evidence of a beneficial effect of creatine monohydrate on survival or disease progression in patients with ALS. Notwithstanding the negative result of the International Study of Infarct Survival-4 (ISIS-4), the controversy about the role of magnesium in acute myocardial infarction is still open because, according to experimental data, magnesium could decrease myocardial damage and mortality only if infusion is started before reperfusion. This randomized placebo-controlled trial was designed to evaluate the effect of intravenous magnesium, delivered before, during, and after direct coronary angioplasty, in patients with acute myocardial infarction.
                One-hundred fifty patients were randomized to intravenous magnesium sulfate or placebo. The primary end point was an infarct zone wall motion score index at 30 days, as a measure of infarct size. The secondary end points included creatine kinase peak, ventricular fibrillation/tachycardia within the first 24 hours, death and congestive heart failure within the 30-day follow-up, and 30-day left ventricular ejection fraction. Analysis was by intention to treat.
                There were no significant differences between the magnesium and placebo groups in the 30-day infarct zone wall motion score index (1.93 +/- 0.61 vs 1.85 +/- 0.51, P =.39), ventricular arrhythmias (24% vs 15%, P =.15), death (0 vs 1%, P =.32), heart failure (8% vs 7%, P =.75), and 30-day left ventricular ejection fraction (49% +/- 11% vs 50% +/- 9%, P = 0.55). There was a trend toward a higher creatine kinase peak in the magnesium group (3059 +/- 2359 vs 2404 +/- 1673,P =.052).
                Intravenous magnesium delivered before, during, and after reperfusion did not decrease myocardial damage and did not improve the short-term clinical outcome in patients with acute myocardial infarction treated with direct angioplasty. Although in experimental models of coronary occlusion diltiazem administration has been shown to reduce the degree of stunning and of reperfusion injury, the majority of clinical trials has failed to demonstrate significant benefits. The aim of this study was to evaluate the effect of diltiazem, administered before coronary reperfusion, on infarct size, residual myocardial viability and recovery of left ventricular function.
                We studied 90 patients admitted within 3 hours of the onset of symptoms of acute myocardial infarction. They were immediately randomized to either intravenous diltiazem (10 mg bolus + 10 mg/hour for 3 days) (group 1, n = 43) or placebo (group 2, n = 47) and subsequently treated with recombinant tissue-type plasminogen activator. All underwent serial echocardiograms upon admission, 4 days post-admission during low-dose dobutamine stress echo, at discharge and after 6 months. We calculated the dysfunction score (1 = hypokinesia, 2 = akinesia, 3 = dyskinesia) on admission and its percent reduction after dobutamine (viability) and at follow-up (recovery). The 12-lead electrocardiograms were continuously monitored for 3 days and coronary angioplasty was performed whenever the residual stenosis was > 60%.
                Upon admission, there were no differences in age, sex, infarct location and size, degree of ST-segment elevation, time from onset of symptoms and dysfunction score. Creatine kinase peaked early in 70% of patients in both groups; the incidences of recurrent ischemia, infarct-related vessel patency and the need for coronary angioplasty were also similar. The creatine kinase peak was significantly higher in group 2 (2931 +/- 2456 vs 1726 +/- 1004 IU/l, p < 0.05). Conversely, in group 1 the residual viability was significantly higher (51 +/- 23 vs 36 +/- 30% improvement in dysfunction score, p < 0.05) and the early recovery of regional function was significantly greater (35 +/- 34 vs 18 +/- 22% at discharge, p < 0.05). On the other hand, the delayed recovery was not significantly different (15 +/- 29 vs 21 +/- 32% from the time of discharge to 6 months of follow-up).
                Intravenous diltiazem, started before coronary reperfusion, has beneficial effects on the infarct size, residual viability and recovery of regional function. If confirmed by larger trials, these preliminary results suggest the use of diltiazem as adjunctive therapy in patients with acute myocardial infarction and undergoing reperfusion. We tested the efficacy and safety of glutamine (0.6 gm/kg/day) and creatine (5 gm/day) in 50 ambulant boys with Duchenne muscular dystrophy in a 6-month, double-blind, placebo-controlled clinical trial. Drug efficacy was tested by measuring muscle strength manually (34 muscle groups) and quantitatively (10 muscle groups). Timed functional tests, functional parameters, and pulmonary function tests were secondary outcome measures. Although there was no statistically significant effect of either therapy based on manual and quantitative measurements of muscle strength, a disease-modifying effect of creatine in older Duchenne muscular dystrophy and creatine and glutamine in younger Duchenne muscular dystrophy cannot be excluded. Creatine and glutamine were well tolerated.
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.