Effect of ranolazine on plasma arginine derivatives and urinary isoprostane 8-iso-PGF2α in patients with myocardial infarction in the randomized RIMINI-Trial.

The purpose of the present study was to assess whether 6-week ranolazine application on top of guideline-based treatment impacts on the arginine/NO pathway and urinary isoprostane 8-iso-PGF2α as marker of oxidative stress in patients directly after a myocardial infarction. 20 patients with unstable angina pectoris and proof of acute cardiac ischemia entered the study. 10 subjects received the study drug ranolazine in addition to standard treatment, the others received only standard treatment. Urine and venous blood were collected before and after treatment. At the end of the study and compared to baseline, homoarginine levels had increased in the control group. This was not the case in ranolazine-patients. Interestingly, in ranolazine-treated-patients arginine plasma levels were significantly higher at the end of the study than at baseline (difference +26 µmol/L, 95% CI 8.6 to 44 µmol/L). ADMA and SDMA levels were not different. Urine levels of the oxidative stress marker 8-iso-PGF2α tended to be lower in ranolazine-treated patients (-144 pmol/mg creatinine). Findings of this hypothesis-driven study give evidence that ranolazine treatment enhances arginine plasma levels and lowers oxidative stress.

Effect of Ranolazine on Ischemic Myocardium IN Patients With Acute Cardiac Ischemia (RIMINI-Trial): A Randomized Controlled Pilot Trial.

BACKGROUND: Coronary artery disease is the most prevalent manifestation among cardiovascular diseases. Despite modern treatment, risk of ischemic complications in patients with acute coronary syndrome (ACS) remains important. The late Na+ current blocker ranolazine has shown to reduce the risk of recurrent ischemia and worsening of angina in patients with non-ST-segment elevation ACS by possibly improving myocardial perfusion, but up to now no trial has addressed whether this enhanced perfusion also leads to a decrease in ischemic myocardium of patients with ACS. We designed a pilot trial (Reduction of Ischemic Myocardium with Ranolazine-Treatment IN patients with acute myocardial Infarction, ClinicalTrials.gov Identifier: NCT01797484) for feasibility and proof of concept that a 6-week ranolazine add-on therapy would reduce the area of ischemic myocardium in patients with ACS. METHODS AND RESULTS: The trial was designed in a 2-armed, controlled and randomized way. Twenty participants with unstable angina, proof of acute cardiac ischemia, and myocardial dyskinesia by speckle-tracking echocardiography were included. Ten participants received the study drug ranolazine additionally to standard treatment. The control group received standard treatment without additional study medication. Speckle-tracking echocardiography was performed before coronary intervention, before the first dose of ranolazine, and after 6 weeks of ranolazine treatment. Ranolazine was administered safely during acute myocardial infarction. Speckle-tracking echocardiography proved to be suitable for evaluation of myocardial dyskinesia. Patients receiving ranolazine showed a trend to higher normal fraction of the cumulative global strain than patients in the standard treatment group (15% vs 11%). No major complications relating study medication were observed. CONCLUSION: In conclusion, in this preliminary hypothesis-driven study, 6-week ranolazine therapy was shown to decrease the area of dyskinetic myocardium in patients with ACS by trend. Global strain rate measurement using speckle-tracking echocardiography can be applied measuring those effects and is, compared to other techniques, safe and harmless. Our data provide a sound basis for a follow-up trial.

Challenging the 99th percentile: A lower troponin cutoff leads to low mortality of chest pain patients.

BACKGROUND: Rule-out of non-ST-elevation myocardial infarction is based on consecutive measurements of cardiac troponins using the 99th percentile of the respective assay as cutoff. The new ESC guidelines alternatively offer rapid 1h algorithms with lower cutoffs than the 99th percentile for rule-out of non-ST-elevation myocardial infarction. We aimed to compare a recently introduced 1h algorithm based on a high-sensitivity cardiac troponin I (hs-TnI) cutoff of 6ng/L at 0h and 1h to the current standard of care using the 99th percentile (27ng/L) as cutoff with reference to follow-up events in a large chest pain cohort. METHODS: Hs-TnI was measured at three time points (0h, 1h and 3h) in 1625 patients presenting with suspected myocardial infarction to the emergency department of the University-Medical Center Hamburg-Eppendorf. Seventy-five patients with ST-elevation myocardial infarction were excluded from the analysis. All-cause mortality, cardiac death, acute myocardial infarction, revascularization and cardiac rehospitalization after 12months were assessed. RESULTS: Patients ruled out by the 1h algorithm showed significantly less cardiac rehospitalizations (12.84% vs. 17.66%; p<0.001), and overall mortality (1.30% vs 3.46%, p<0.001) compared to using the 99th percentile as cutoff. The majority of deaths were caused by non-cardiac reasons. Cardiac deaths were rare using the 1h algorithm (0.21%). CONCLUSION: The commonly used 99th percentile as cutoff neglects patients with a high risk in the setting of acute chest pain. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT02355457).

Immediate Rule-Out of Acute Myocardial Infarction Using Electrocardiogram and Baseline High-Sensitivity Troponin I.

AIMS: Serial measurements of high-sensitivity troponin are used to rule out acute myocardial infarction (AMI) with an assay specific cutoff at the 99th percentile. Here, we evaluated the performance of a single admission troponin with a lower cutoff combined with a low risk electrocardiogram (ECG) to rule out AMI. METHODS: Troponin I measured with a high-sensitivity assay (hs-TnI) was determined at admission in 1040 patients presenting with suspected AMI (BACC study). To rule out AMI we calculated the negative predictive value (NPV) utilizing the optimal hs-TnI cutoff combined with a low risk ECG. The results were validated in 3566 patients with suspected AMI [2-h Accelerated Diagnostic Protocol to Assess Patients With Chest Pain Symptoms Using Contemporary Troponins as the Only Biomarker (ADAPT) studies]. Patients were followed for 6 or 12 months. RESULTS: 184 of all patients were diagnosed with AMI. An hs-TnI cutoff of 3 ng/L resulted in a NPV of 99.3% (CI 97.3-100.0), ruling out 35% of all non-AMI patients. Adding the information of a low risk ECG resulted in a 100% (CI 97.5-100.0) NPV (28% ruled out). The 2 validation cohorts replicated the high NPV of this approach. The follow-up mortality in the ruled out population was low (0 deaths in BACC and Stenocardia, 1 death in ADAPT). CONCLUSIONS: A single hs-TnI measurement on admission combined with a low risk ECG appears to rule out AMI safely without need for serial troponin testing. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT02355457).

Diagnosis of Myocardial Infarction Using a High-Sensitivity Troponin I 1-Hour Algorithm.

IMPORTANCE: Rapid and accurate diagnosis of acute myocardial infarction (AMI) currently constitutes an unmet need. OBJECTIVE: To test a 1-hour diagnostic algorithm to diagnose AMI using a high-sensitivity troponin I assay with a new cutoff level of 6 ng/L. DESIGN, SETTING, AND PARTICIPANTS: The Biomarkers in Acute Cardiac Care study is a prospective study that investigated the application of the troponin I assay for the diagnosis of AMI in 1040 patients presenting to the emergency department with acute chest pain from July 19, 2013, to December 31, 2014. Results were validated in 2 independent cohorts of 4009 patients. Final follow-up was completed on July 1, 2015, and data were assessed from July 2 to December 15, 2015. EXPOSURE: Acute chest pain suggestive of AMI. MAIN OUTCOMES AND MEASURES: Accurate diagnosis or exclusion of AMI and 12-month mortality in patients with acute chest pain. RESULTS: Of the 1040 patients included from the study cohort, 673 (64.7%) were male and had a median age of 65 (interquartile range, 52-75) years. With application of a low troponin I cutoff value of 6 ng/L, the rule-out algorithm showed a high negative predictive value of 99.8% (95% CI, 98.6%-100.0%) after 1 hour for non-ST-segment elevation MI type 1. The 1-hour approach was comparable to a 3-hour approach. Similarly, a rule-in algorithm based on troponin I levels provided a high positive predictive value with 82.8% (95% CI, 73.2%-90.0%). Moreover, application of the cutoff of 6 ng/L resulted in lower follow-up mortality (1.0%) compared with the routinely used 99th percentile (3.7%) for this assay. Two independent cohorts further validated the performance of this algorithm with high negative and positive predictive values. CONCLUSIONS AND RELEVANCE: Patients with possible AMI can be triaged within 1 hour after admission with no loss of safety compared with a 3-hour approach, when a low and sensitive cutoff is applied. This concept enables safe discharge or rapid treatment initiation after 1 hour.

Low energy biphasic cardioversion of atrial flutter: results from a pilot trial.

A pilot study was performed to determine the efficacy of low energy biphasic external cardioversion in common type atrial flutter. In the majority of patients (70%) successful cardioversion was achieved with low energy levels of 20 or 30 J; however a considerable number of patients (15%) were initially cardioverted to atrial fibrillation, needing an additional cardioversion with an even higher energy level.

Comparison of antero-lateral versus antero-posterior electrode position for biphasic external cardioversion of atrial flutter.

External cardioversion is an established and very important tool to terminate symptomatic atrial flutter. The superiority of the biphasic waveform has been demonstrated for atrial flutter, but whether electrode position affects the efficacy of cardioversion in this population is not known. The aim of this trial was to evaluate whether anterior-lateral (A-L) compared with anterior-posterior (A-P) electrode position improves cardioversion results. Of 130 screened patients, 96 (72 men, mean age 62 +/- 12 years) were included and randomly assigned to a cardioversion protocol with either A-L or A-P electrode position. In each group, 48 patients received sequential biphasic waveform shocks using a step-up protocol consisting of 50, 75, 100, 150, or 200 J. The mean energy (65 +/- 13 J for A-L vs 77 +/- 13 J for A-P, p = 0.001) and mean number of shocks (1.48 +/- 1.01 for A-L vs 1.96 +/- 1.00 for A-P, p = 0.001) required for successful cardioversion were significantly lower in the A-L group. The efficacy of the first shock with 50 J in the A-L electrode position (35 of 48 patients [73%]) was also highly significantly greater than the first shock with 50 J in the A-P electrode position (18 of 48 patients [36%]) (p = 0.001). In conclusion, the A-L electrode position increases efficacy and requires fewer energy and shocks in external electrical cardioversion of common atrial flutter. Therefore, A-L electrode positioning should be recommended for the external cardioversion of common atrial flutter.

Biphasic versus monophasic shock for external cardioversion of atrial flutter: a prospective, randomized trial.

BACKGROUND: External cardioversion is effective to terminate persistent atrial flutter. Biphasic shocks have been shown to be superior to monophasic shocks for ventricular defibrillation and atrial fibrillation cardioversion. The purpose of this trial was to compare the efficacy of rectilinear biphasic versus standard damped sine wave monophasic shocks in symptomatic patients with typical atrial flutter. METHODS: 135 consecutive patients were screened, 95 (70 males, mean age 62 +/- 13 years) were included. Patients were randomly assigned to a monophasic or biphasic cardioversion protocol. Forty-seven patients randomized to the monophasic protocol received sequential shocks of 100, 150, 200, 300 and 360 J. Forty-eight patients with the biphasic protocol received 50, 75, 100, 150 or 200 J. RESULTS: First-shock efficacy with 50-Joule, biphasic shocks (23/48 patients, 48%) was significantly greater than with the 100-Joule, monophasic waveform (13/47 patients, 28%, p = 0.04). The cumulative second-shock efficacy with the 50- and 75-Joule, biphasic waveform (39/48 patients, 81%) was significantly greater than with the 100- and 150-Joule, monophasic waveform (25/47 patients, 53%, p < 0.05). The cumulative efficacy for the higher energy levels showed naturally no significant difference between the two groups. The amount of the mean delivered energy was significantly lower in the biphasic group (76 +/- 39 J) compared to the monophasic one (177 +/- 78 J, p < 0.05). CONCLUSIONS: For transthoracic cardioversion of typical atrial flutter, biphasic shocks have greater efficacy and the mean delivered current is lower than for monophasic shocks. Therefore, biphasic cardioversion with lower starting energies should be recommended.