The Benefit of Insulin Degludec/Liraglutide (IDegLira) Compared With Basal-Bolus Insulin Therapy is Consistent Across Participant Subgroups With Type 2 Diabetes in the DUAL VII Randomized Trial.

BACKGROUND: Insulin degludec/liraglutide (IDegLira) results in glycated hemoglobin (HbA1c) levels comparable with basal-bolus (BB) therapy. Here, we assessed the effect of once-daily IDegLira compared with BB (once-daily insulin glargine 100 U/mL and insulin aspart ≤4 times/day) across subgroups with varying characteristics. MATERIALS AND METHODS: DUAL VII trial participants (type 2 diabetes [T2D], HbA1c 53-86 mmol/mol [7.0%-10.0%]) were subgrouped post hoc based on the following baseline characteristics: HbA1c (≤58.5, >58.5 to ≤69.4, and >69.4 mmol/mol; ≤7.5%, >7.5 to ≤8.5%, and >8.5%), body mass index (<30, ≥30 to <35, and ≥35 kg/m2), age (18 to <65 and ≥65 years), duration of diabetes (≥0 to 10 and ≥10 years), total pretrial daily basal insulin dose (20 to <30, ≥30 to <40, and ≥40 to ≤50 U), and fasting plasma glucose (<7.2 mmol/L/<130 mg/dL and ≥7.2 mmol/L/≥130 mg/dL). RESULTS: Compared with BB, and in all subgroups, IDegLira treatment consistently gave similar HbA1c reductions, less severe or blood glucose-confirmed hypoglycemia, lower end-of-trial (EOT) total daily insulin dose, and weight loss. In all subgroups, mean EOT HbA1c was ≤53 mmol/mol (≤7.0%). The greatest HbA1c reduction occurred in the highest baseline HbA1c subgroup. Overall, mean EOT daily insulin dose was 0.43 to 0.52 U/kg with IDegLira and 0.74 to 1.07 U/kg with BB. More participants achieved the triple composite endpoint (HbA1c <53 mmol/mol [<7.0%] without weight gain or hypoglycemia) with IDegLira vs BB across the baseline HbA1c subgroups (≤58.5 mmol/mol [44.6% vs 7.0%], >58.5 to ≤69.4 mmol/mol [41.1% vs 8.3%], and >69.4 mmol/mol [23.8% vs 3.4%]). CONCLUSION: These results support initiating IDegLira in patients with varying baseline characteristics and uncontrolled T2D on basal insulin. CLINICALTRIALS.GOV REGISTRATION: NCT02420262.

A greater proportion of participants with type 2 diabetes achieve treatment targets with insulin degludec/liraglutide versus insulin glargine 100 units/mL at 26 weeks: DUAL VIII, a randomized trial designed to resemble clinical practice.

This report presents the efficacy and safety of insulin degludec/liraglutide (IDegLira) versus insulin glargine 100 units/mL (IGlar U100) as initial injectable therapy at 26 weeks in the 104-week DUAL VIII durability trial (NCT02501161). Participants (N = 1012) with type 2 diabetes (T2D) uncontrolled on oral antidiabetic drugs (OADs) were randomized 1:1 to open-label IDegLira or IGlar U100. Visits were scheduled at weeks 1, 2, 4 and 12, and every 3 months thereafter. After 26 weeks, glycated haemoglobin (HbA1c) reductions were greater with IDegLira versus IGlar U100 (-21.5 vs. -16.4 mmol/mol [-2.0 vs. -1.5%]), as was the percentage of participants achieving HbA1c <53 mmol/mol (78.7% vs. 55.7%) and HbA1c targets without weight gain and/or hypoglycaemia. Estimated treatment differences for insulin dose (-13.01 U) and body weight change (-1.57 kg) significantly favoured IDegLira. The hypoglycaemia rate was 44% lower with IDegLira versus IGlar U100. Safety results were similar. In a trial resembling clinical practice, more participants receiving IDegLira than IGlar U100 met treatment targets, supporting use of IDegLira as an initial injectable therapy for people with T2D uncontrolled on OADs and eligible for insulin initiation.

Durability of insulin degludec plus liraglutide versus insulin glargine U100 as initial injectable therapy in type 2 diabetes (DUAL VIII): a multicentre, open-label, phase 3b, randomised controlled trial.

BACKGROUND: Durability of glycaemic control might reduce disease burden and improve long-term outcomes. DUAL VIII investigated the durability of insulin degludec plus liraglutide (IDegLira) versus insulin glargine 100 units/mL (IGlar U100) in patients with type 2 diabetes with the use of a visit schedule that mirrored routine clinical practice. METHODS: In this 104-week international, multicentre, open-label, phase 3b randomised controlled trial, insulin-naive patients aged 18 years and older, with HbA1c between 7·0-11·0% (53-97 mmol/mol), BMI of 20 kg/m2 or higher, on stable doses of oral antidiabetic drugs, were recruited from outpatient clinics. Patients were randomly assigned 1:1, with a simple sequential allocation randomisation schedule (block size of four), to IDegLira or IGlar U100, each treatment being an add-on to existing therapy. The internal safety committee, the independent external committee, and the personnel involved in defining the analysis sets were masked until the database was released for statistical analysis. Patients and all other investigators were not masked. In the IDegLira group, patients were given degludec 100 units/mL plus liraglutide 3·6 mg/mL in a 3 mL prefilled PDS290 pen for subcutaneous injection; in the IGlar U100 group, patients were given IGlar U100 solution, in a 3 mL prefilled Solostar pen for subcutaneous injection. Both treatments were given once daily at any time of day and it was recommended that the time of day remained the same throughout the trial. The primary endpoint was time from randomisation to need for treatment intensification (HbA1c ≥7·0% [53 mmol/mol] at two consecutive visits, including week 26). Once patients met this criterion, the trial product was permanently discontinued and patients were not withdrawn from trial but rather remained on follow-up for the entire treatment and follow-up period. The primary analysis was in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT02501161. FINDINGS: From Jan 8, 2016, to Oct 3, 2018, 1345 patients were screened, of which 1012 (75·2%) were eligible and randomly assigned to either IDegLira (n=506) or IGlar U100 (n=506). 484 (96%) of 506 in the IDegLira group and 481 (95%) of 506 in the IGlar U100 group completed the trial. Baseline characteristics were similar and representative of patients eligible for basal insulin intensification (overall mean diabetes duration 10 years; HbA1c 8·5% [69 mmol/mol]; fasting plasma glucose 10 mmol/L). Patients in the IDegLira group had significantly longer time until intensification was needed than those in the IGlar U100 group (median >2 years vs about 1 year). Fewer patients in the IDegLira group needed treatment intensification over 104 weeks than those in the IGlar U100 group (189 [37%] of 506 vs 335 [66%] of 506). The preplanned sensitivity analyses of the primary endpoint were in agreement with the primary analysis (hazard ratio 0·45 [95% CI 0·38-0·54]) in the proportional hazards regression model and the generalised log-rank test was also in favour of IDegLira (p<0·0001). No new or unexpected safety and tolerability issues were identified and there were no treatment-related deaths. INTERPRETATION: In patients with uncontrolled type 2 diabetes on oral antidiabetic drugs, initial injectable therapy with IDegLira resulted in fewer patients reaching the treatment intensification criterion during 104 weeks versus IGlar U100, with longer durability of the treatment effect with IDegLira. FUNDING: Novo Nordisk.

Superior efficacy of insulin degludec/liraglutide versus insulin glargine U100 as add-on to sodium-glucose co-transporter-2 inhibitor therapy: A randomized clinical trial in people with uncontrolled type 2 diabetes.

AIM: To investigate the efficacy and safety of insulin degludec/liraglutide (IDegLira) versus insulin glargine 100 units/mL (IGlar U100) as add-on to sodium-glucose co-transporter-2 (SGLT2) inhibitor therapy. MATERIALS AND METHODS: In this 26-week, phase IIIb, open-label, parallel-group, treat-to-target trial, conducted at 74 sites in 11 countries, insulin-naïve people aged ≥18 years with glycated haemoglobin (HbA1c) 53-97 mmol/mol (7.0-11.0%), body mass index 20-40 kg/m2 and inadequately controlled type 2 diabetes (T2D) on SGLT2 inhibitor ± oral antidiabetic drugs were randomized 1:1 to once-daily IDegLira or IGlar U100, both as add-on to existing therapy. The primary endpoint was change in HbA1c from baseline to week 26. RESULTS: A total of 210 participants were randomized to each treatment arm. Mean HbA1c reductions were 21 mmol/mol (1.9%-points) with IDegLira and 18 mmol/mol (1.7%-points) with IGlar U100; confirming non-inferiority (P < 0.0001) and superiority of IDegLira (difference in HbA1c change -3.90 mmol/mol; 95% confidence interval [CI] -5.45; -2.35 (-0.36%-points; 95% CI -0.50, -0.21)). Superiority for IDegLira over IGlar U100 was also confirmed for: body weight (difference -1.92 kg; 95% CI -2.64, -1.19); severe or blood-glucose-confirmed symptomatic hypoglycaemia (rate ratio 0.42; 95% CI 0.23, 0.75); total daily insulin dose (difference -15.37 U; 95% CI -19.60, -11.13). The overall treatment-emergent adverse event rate was higher with IDegLira as a result of higher increased lipase and nausea rates. CONCLUSIONS: The favourable safety and efficacy profile of IDegLira in people with uncontrolled T2D on SGLT2 inhibitors, and lower weight gain and hypoglycaemia risk versus IGlar U100, suggest that clinicians should consider IDegLira initiation in this population.

EFFICACY AND SAFETY OF IDEGLIRA IN OLDER PATIENTS WITH TYPE 2 DIABETES.

OBJECTIVE: The efficacy and safety of insulin degludec/liraglutide (IDegLira) in older patients has not yet been reported. This analysis aimed to evaluate the efficacy and safety of IDegLira in patients aged ≥65 years. METHODS: A post hoc analysis compared results of patients aged ≥65 versus <65 years from DUAL II, III, and V. These were 26-week, phase 3, randomized, twoarm parallel, treat-to-target trials in patients already taking injectable glucose-lowering agents. We evaluated 311 patients aged <65 and 87 patients aged ≥65 years from DUAL II, 326 patients <65 years and 112 patients ≥65 years from DUAL III, and 412 patients <65 years and 145 patients ≥65 years from DUAL V. Patients were randomized to IDegLira or insulin degludec (DUAL II), IDegLira or unchanged glucagon-like peptide 1-receptor agonist (GLP-1RA) (DUAL III), or IDegLira or IGlar U100 (DUAL V). RESULTS: In patients ≥65 years, hemoglobin A1C decreased to a greater extent with IDegLira than with comparators (estimated treatment differences, -1.0% [-1.5; -0.6]95% confidence interval [CI], -0.8% [-1.0; -0.5]95% CI, and -0.9% [-1.3; -0.6]95%CI) for DUAL II, V, and III, respectively; all P<.001). These mirrored results of patients <65 years of age. Hypoglycemia rates were lower with IDegLira versus basal insulin and higher versus unchanged GLP-1RA (estimated rate ratios, 0.5 [0.2; 1.6]95% CI [ P = .242]; 0.3 [0.1; 0.5]95% CI [ P<.001], and 11.8 [3.3; 42.8]95% CI [ P<.001] for DUAL II, V, and III, respectively). CONCLUSION: Patients aged ≥65 years on basal insulin or GLP-1RA can improve glycemic control with IDegLira, and it is well tolerated overall. ABBREVIATIONS: A1C = hemoglobin A1C; AE = adverse event; CI = confidence interval; Degludec = insulin degludec; EOT = end of trial; ETD = estimated treatment difference; FPG = fasting plasma glucose; GLP-1RA = glucagon-like peptide 1 receptor agonist; IDegLira = insulin degludec/liraglutide; IGlar U100 = insulin glargine 100 U/mL; SU = sulfonylurea; T2D = type 2 diabetes.

Efficacy and Safety of IDegLira Versus Basal-Bolus Insulin Therapy in Patients With Type 2 Diabetes Uncontrolled on Metformin and Basal Insulin: The DUAL VII Randomized Clinical Trial.

OBJECTIVE: In patients with uncontrolled type 2 diabetes on basal insulin, prandial insulin may be initiated. We assessed the efficacy and safety of initiating insulin degludec/liraglutide fixed-ratio combination (IDegLira) versus basal-bolus insulin. RESEARCH DESIGN AND METHODS: A phase 3b trial examined patients with uncontrolled type 2 diabetes on insulin glargine (IGlar U100) 20-50 units/day and metformin, randomized to IDegLira or IGlar U100 and insulin aspart ≤4 times per day. RESULTS: Glycated hemoglobin (HbA1c) decreased from 8.2% (66 mmol/mol) to 6.7% (50 mmol/mol) with IDegLira and from 8.2% (67 mmol/mol) to 6.7% (50 mmol/mol) with basal-bolus (estimated treatment difference [ETD] -0.02% [95% CI -0.16, 0.12]; -0.2 mmol/mol [95% CI -1.7, 1.3]), confirming IDegLira noninferiority versus basal-bolus (P < 0.0001). The number of severe or blood glucose-confirmed symptomatic hypoglycemia events was lower with IDegLira versus basal-bolus (risk ratio 0.39 [95% CI 0.29, 0.51]; rate ratio 0.11 [95% CI 0.08, 0.17]). Body weight decreased with IDegLira and increased with basal-bolus (ETD -3.6 kg [95% CI -4.2, -2.9]). Fasting plasma glucose reductions were similar; lunch, dinner, and bedtime self-monitored plasma glucose measurements were significantly lower with basal-bolus. Sixty-six percent of patients on IDegLira vs. 67.0% on basal-bolus achieved HbA1c <7.0% (53 mmol/mol). Total daily insulin dose was lower with IDegLira (40 units) than basal-bolus (84 units total; 52 units basal). CONCLUSIONS: In patients with uncontrolled type 2 diabetes on IGlar U100 and metformin, IDegLira treatment elicited HbA1c reductions comparable to basal-bolus, with statistically superior lower hypoglycemia rates and weight loss versus weight gain.

Effect of Intracoronary and Intravenous Melatonin on Myocardial Salvage Index in Patients with ST-Elevation Myocardial Infarction: a Randomized Placebo Controlled Trial.

Melatonin has attenuated myocardial ischemia reperfusion injury in experimental studies. We hypothesized that the administration of melatonin during acute myocardial reperfusion improves myocardial salvage index in patients with ST-elevation myocardial infarction. Patients (n = 48) were randomized in a 1:1 ratio to intracoronary and intravenous melatonin (total 50 mg) or placebo. The myocardial salvage index assessed by cardiac magnetic resonance imaging at day 4 (± 1 day) after primary percutaneous coronary intervention was similar in the melatonin group (n = 22) at 55.3% (95% CI 47.0-63.6) and the placebo group (n = 19) at 61.5% (95% CI 57.5-65.5), p = 0.21. The levels of high-sensitive troponin T, creatinine kinase myocardial band, and oxidative biomarkers (advanced oxidation protein products, malondialdehyde, myeloperoxidase) were similar in the groups. The frequency of clinical events at 90 days did not differ between the groups. In conclusion, melatonin did not improve the myocardial salvage index after primary percutaneous coronary intervention in patients with ST elevation myocardial infarction compared with placebo.

Safety and efficacy of IDegLira titrated once weekly versus twice weekly in patients with type 2 diabetes uncontrolled on oral antidiabetic drugs: DUAL VI randomized clinical trial.

AIMS: To compare the safety and efficacy of a simpler titration algorithm for insulin degludec/liraglutide (IDegLira) with that used in previous DUAL trials in insulin-naïve patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This 32-week, open-label, non-inferiority trial randomized adults with type 2 diabetes uncontrolled on metformin ± pioglitazone to receive IDegLira, titrated either once weekly, based on the mean of 2 pre-breakfast plasma glucose (PG) readings (n = 210), or twice weekly, based on the mean of 3 pre-breakfast PG readings (n = 210). RESULTS: Mean HbA1c decreased from 8.2% (65 mmol/mol) to 6.1% (43 mmol/mol) with once-weekly titration and from 8.1% (65 mmol/mol) to 6.0% (42 mmol/mol) with twice-weekly titration; non-inferiority was confirmed (estimated treatment difference: 0.12% [-0.04; 0.28]95%CI , 1.30 mmol/mol [-0.41; 3.01]95%CI ). Approximately 90% of patients achieved HbA1c < 7% in each arm. Mean fasting PG was similar after 32 weeks. Weight change was -1.0 kg vs -2.0 kg for once-weekly vs twice-weekly titration. Rates of severe or blood glucose-confirmed symptomatic hypoglycaemia were low in both arms: 0.16 events/patient-year of exposure (PYE) for once-weekly, 0.76 events/PYE for twice-weekly titration. Mean IDegLira dose at 32 weeks was 41 dose steps (41 U IDeg/1.48 mg Lira) for both arms. Overall adverse event rates were 207.8 and 241.3 events/100 PYE with once-weekly and twice-weekly titration, respectively. CONCLUSION: A pragmatic titration algorithm with once-weekly adjustments based on 2 PG readings resulted in a safety and glycaemic efficacy profile similar to that with twice-weekly adjustments based on 3 preceding PG values in insulin-naïve patients.

An adverse drug event manager facilitates spontaneous reporting of adverse drug reactions.

INTRODUCTION: Spontaneous reporting of adverse drug reactions (ADRs) is used for continuous risk-benefit evaluation of marketed pharmaceutical products and for signal detection. The Adverse Drug Event Manager (ADEM) is a service offered to clinicians employed at hospitals in the Capital Region of Denmark. The ADEM assists healthcare professionals in reporting suspected ADRs to the Danish Health Authority. The aim of this retrospective observational study was to quantify and describe ADRs reported via the ADEM in 2014. METHODS: All ADR reports handled by the ADEM in 2014 were recorded anonymously and analysed descriptively. RESULTS: A total of 484 ADRs were reported through the ADEM in 2014 (the median number of reports per month was 37; range: 17-78). The majority of the reports came from departments of internal medicine (61%), psychiatry (14%) and dermatology, ophthalmology or otorhinolaryngology (11%). The drugs most frequently reported were lisdexamphetamine (n = 40), rivaroxaban (n = 16) and warfarin (n = 15) (vaccines excluded). In 13 out of 484 reports, the ADR was associated with a fatal outcome. CONCLUSION: The findings of this study indicate that an ADEM promotes and facilitates spontaneous ADR reporting and helps raise awareness about ADRs, including how and why they should be reported. Hopefully, this will assist national and European spontaneous reporting systems in their work to increase patient safety nationally and abroad. FUNDING: none. TRIAL REGISTRATION: not relevant. .

Effects of intracoronary melatonin on ischemia-reperfusion injury in ST-elevation myocardial infarction.

Acute coronary occlusion is effectively treated by primary percutaneous coronary intervention. However, myocardial ischemia-reperfusion injury is at the moment an unavoidable consequence of the procedure. Oxidative stress is central in the development of ischemia-reperfusion injury. Melatonin, an endogenous hormone, acts through antioxidant mechanisms and could potentially minimize the myocardial injury. The aim of the experimental study was to examine the cardioprotective effects of melatonin in a porcine closed-chest reperfused infarction model. A total of 20 landrace pigs were randomized to a dosage of 200 mg (0.4 mg/mL) melatonin or placebo (saline). The intervention was administered intracoronary and intravenous. Infarct size, area at risk and microvascular obstruction were determined ex vivo by cardiovascular magnetic resonance imaging. Myocardial salvage index was calculated. The plasma levels of high-sensitive troponin T were assessed repeatedly. The experimenters were blinded with regard to treatment regimen. Melatonin did not significantly increase myocardial salvage index compared with placebo [melatonin 21.8% (16.1; 24.8) vs. placebo 20.2% (16.9; 27.0), p = 1.00]. The extent of microvascular obstruction was similar between the groups [melatonin 3.8% (2.7; 7.1) vs. placebo 3.7% (1.3; 7.7), p = 0.96]. The area under the curve for high-sensitive troponin T release was insignificantly reduced by 32% in the melatonin group [AUC melatonin 12,343.9 (6,889.2; 20,147.4) ng h/L vs. AUC placebo 18,285.3 (5,180.4; 23,716.8) ng h/L, p = 0.82]. Combined intracoronary and intravenous treatment with melatonin did not reduce myocardial reperfusion injury. The lack of a positive effect could be due to an ineffective dose of melatonin, a type II error or the timing of administration.

Oxidative and inflammatory biomarkers of ischemia and reperfusion injuries.

Ischemia-reperfusion injuries occur when the blood supply to an organ or tissue is temporarily cut-off and then restored. Even though the restoration of blood flow is absolutely essential in preventing tissue death, the reperfusion of oxygenated blood to the oxygen-deprived areas may in itself augment the tissue damage in excess of that produced by the ischemia alone. The process of ischemia-reperfusion is multifactorial and there are several mechanisms involved in the pathogenesis. Ample evidence shows that the injury is in part caused by an excessive generation of reactive oxygen species or free radicals. The free radicals consequently initiate an inflammatory response, which in some cases may affect distant organs, thus causing remote organ injuries. Ischemia-reperfusion injuries are a common complication in many diseases (acute myocardial infarctions, stroke) or surgical settings (transplantations, tourniquet-related surgery) and they have potential detrimental and disabling consequences. The tolerance of ischemia-reperfusion has proven to be time-of-day-dependent and the size of myocardial infarctions has proven to be significantly higher when occurring in the dark-to-light period. This period is characterized by and coincides with a rapid decrease in the plasma levels of the hormone melatonin. Melatonin is the body's most potent antioxidant and is capable of both direct free radical scavenging and indirect optimization of other anti-oxidant enzymes. It also possesses anti-inflammatory properties and is known to inhibit the mitochondrial permeability transition pore during reperfusion. This inhibiting property has been shown to be of great importance in reducing ischemia-reperfusion injuries. Furthermore, melatonin is a relatively non-toxic molecule, which has proven to be safe for use in clinical trials. Thus, there is compelling evidence of melatonin's effect in reducing ischemia-reperfusion injuries in many experimental studies, but the number of human clinical trials is very limited. In this PhD thesis we set out to explore the oxidative and inflammatory biochemical markers of ischemia and reperfusion injuries and the possible effect of melatonin on these markers. We have reviewed the literature on the tourniquet-related oxidative damage and found that ischemic preconditioning and the use of propofol could significantly reduce the release of such markers. However, the relevance of this reduction in terms of clinical outcomes is still to be investigated (paper 1). We undertook the characterization of a human ischemia-reperfusion model without the influencing factors of surgery and anesthesia, and subsequently found ways to improve this model (paper 2). In order to apply an intracoronary melatonin administration, we investigated whether melatonin could be dissolved in non-ethanol based buffers and still activate the melatonin receptors (paper 3). We found this to be possible, and in a porcine closed-chest model of acute myocardial infarction (AMI) we randomized the pigs to intracoronary and systemic melatonin or placebo in order to test whether melatonin could attenuate the oxidative and inflammatory biomarkers following reperfusion (paper 4). The outcomes were not optimal for this model, and the effect of melatonin still remains to be explored in a large animal model. We are currently still awaiting the results of the IMPACT-trial - a randomized, placebo-controlled, clinical trial exploring the effect of intracoronary and systemic melatonin given to patients suffering from AMI and undergoing primary percutaneous coronary intervention (pPCI) (paper 5). Though pPCI is undisputedly life-saving, it holds a built-in consequence of aggravating the ischemic injury, paradoxically due to the reperfusion. The optimization of existing treatments and the exploring of new suitable interventions, such as melatonin, for minimizing the ischemia-reperfusion injuries is therefore of great interest.

Melatonin for pre- and postoperative anxiety in adults.

BACKGROUND: Anxiety in relation to surgery is a well-known problem. Melatonin offers an atoxic alternative to benzodiazepines in ameliorating this condition in the pre- and postoperative period. OBJECTIVES: To assess the effect of melatonin on pre- and postoperative anxiety in adults when comparing melatonin with placebo or when comparing melatonin with benzodiazepines. SEARCH METHODS: The following databases were searched on 19 April 2013: CENTRAL, MEDLINE, EMBASE, CINAHL and Web of Science. For ongoing trials and protocols we searched clinicaltrials.gov, Current Controlled Trials and the World Health Organization (WHO) International Clinical Trials Registry Platform. We reran the search in October 2014. We will deal with any studies of interest when we update the review. SELECTION CRITERIA: Randomized, placebo-controlled or standard treatment-controlled, or both, studies that evaluated the effect of preoperatively administered melatonin on preoperative or postoperative anxiety. We included adult patients of both genders (15 to 90 years of age) undergoing any kind of surgical procedure in which it was necessary to use general, regional or topical anaesthesia. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two review authors. Data extracted included information about study design, country of origin, number of participants and demographic details, type of surgery, type of anaesthesia, intervention and dosing regimen, preoperative anxiety outcome measures and postoperative anxiety outcome measures. MAIN RESULTS: This systematic review identified 12 randomized controlled trials (RCTs) including 774 patients that assessed melatonin for treating preoperative anxiety, postoperative anxiety or both. Four of the 12 studies compared melatonin, placebo and midazolam, whereas the remaining eight studies compared melatonin and placebo only.The quality of the evidence for our primary outcome (melatonin versus placebo for preoperative anxiety) was high. More than half of the included studies had a low risk of selection bias and at least 75% of the included studies had a low risk of attrition, performance and detection bias. Most of the included studies had an unclear risk of reporting bias.Eight out the 10 studies that assessed the effect of melatonin on preoperative anxiety using a visual analogue scale (VAS) (ranging from 0 to 100 mm, higher scores indicate greater anxiety) showed a reduction compared to placebo. The reported estimate of effect (relative effect -13.36, 95% confidence interval (CI) -16.13 to -10.58; high quality evidence) was based on a meta-analysis of seven studies. Two studies did not show any difference between melatonin and placebo. Two studies comparing melatonin with midazolam using a VAS found no evidence of a difference in preoperative anxiety between the two groups (relative effect -1.18, 95% CI -2.59 to 0.23; low quality evidence).Eight studies assessed the effect of melatonin on postoperative anxiety. Four of these studies measuring postoperative anxiety 90 minutes postoperatively using a VAS did not find any evidence of a difference between melatonin and placebo (relative effect -3.71, 95% CI -9.26 to 1.84). Conversely, two studies showed a reduction of postoperative anxiety measured six hours after surgery using the State-Trait Anxiety Inventory (STAI) when comparing melatonin with placebo (relative effect -5.31, 95% CI -8.78 to -1.84; moderate quality evidence). Two studies comparing melatonin with midazolam using a VAS did not find any evidence of a difference between the two groups in postoperative anxiety (relative effect -2.02, 95% CI -5.82 to 1.78). AUTHORS' CONCLUSIONS: When compared to placebo, melatonin given as premedication (tablets or sublingually) can reduce preoperative anxiety in adults (measured 50 to 100 minutes after administration). Melatonin may be equally as effective as standard treatment with midazolam in reducing preoperative anxiety in adults (measured 50 to 100 minutes after administration). The effect of melatonin on postoperative anxiety (measured 90 minutes and 6 hours after surgery) in adults is mixed but suggests an overall attenuation of the effect compared to preoperatively.

Melatonin does not affect oxidative/inflammatory biomarkers in a closed-chest porcine model of acute myocardial infarction.

AIM: To test whether melatonin reduces oxidative and inflammatory biomarkers in a closed-chest porcine model of acute myocardial infarction. MATERIALS AND METHODS: Twenty pigs were randomized to receive a total dosage of 200 mg (0.4 mg/ml) of melatonin, or placebo immediately prior to reperfusion of a coronary artery balloon occlusion in a randomized, observer-blinded, placebo-controlled trial. We assessed high-sensitivity troponin T (hs-TnT), malondialdehyde and interleukin-1b, -6 and -10 at baseline, 30 min and 1, 2, 3 and 4 h after the start of reperfusion. RESULTS: Seventeen pigs completed the trial. There was an increase in hs-TnT, but no significant difference between the melatonin-treated and placebo-treated groups. There were no significant differences in development of any of the circulating plasma markers between the two groups. CONCLUSION: Melatonin treatment did not result in reduction of inflammatory or oxidative stress markers after experimental myocardial infarction compared to placebo.

Intracoronary and systemic melatonin to patients with acute myocardial infarction: protocol for the IMPACT trial.

INTRODUCTION: Ischaemia-reperfusion injury following acute myocardial infarctions (AMI) is an unavoidable consequence of the primary percutaneous coronary intervention (pPCI) procedure. A pivotal mechanism in ischaemia-reperfusion injury is the production of reactive oxygen species following reperfusion. The endogenous hormone, melatonin, works as an antioxidant and could potentially minimise the ischaemia-reperfusion injury. Given intracoronarily, it enables melatonin to work directly at the site of reperfusion. We wish to test if melatonin, as an antioxidant, can minimise the reperfusion injury following pPCI in patients with AMI. MATERIAL AND METHODS: The IMPACT trial is a multicentre, randomised, double-blinded, placebo-controlled study. We wish to include 2 × 20 patients with ST-elevation myocardial infarctions undergoing pPCI within six hours from symptom onset. The primary end-point is the Myocardial Salvage Index assessed by cardiovascular magnetic resonance imaging on day 4 (± 1) after pPCI. The secondary end-points are high-sensitivity troponin, creatinekinase myocardial band and clinical events. CONCLUSION: The aim of the IMPACT trial is to evaluate the effect of melatonin on reperfusion injuries following pPCI. Owing to its relatively non-toxic profile, melatonin is an easily implementable drug in the clinical setting, and melatonin has the potential to reduce morbidity in patients with AMI. FUNDING: This study received no financial support from the industry. TRIAL REGISTRATION: www.clinicaltrials.gov, clinical trials identifier: NCT01172171.

[Closed-chest porcine model is superior in intervention studies of ischaemia reperfusion injury]. / Closed-chest-grisemodellen er overlegen ved interventionsstudier af iskæmireperfusionsskade.

Ischaemia reperfusion injury affects the patients' clinical outcomes. An animal model is therefore required in order to test pharmacological interventions and improve the current treatment of acute myocardial infarction (AMI). This review focuses on the endovascular closed-chest porcine model of ischaemia and reperfusion. In contrast to the open-chest porcine model the closed-chest model closely mimics the clinical situation of an AMI and makes it possible to extrapolate the results directly to humans. The model is well suited for future interventional studies.