Alf-Inge Larsen

Drug-Eluting or Bare-Metal Stents for Coronary Artery Disease

BACKGROUND Limited data are available on the long-term effects of contemporary drug-eluting stents versus contemporary bare-metal stents on rates of death, myocardial infarction, repeat revascularization, and stent thrombosis and on quality of life. METHODS We randomly assigned 9013 patients who had stable or unstable coronary artery disease to undergo percutaneous coronary intervention (PCI) with the implantation of either contemporary drug-eluting stents or bare-metal stents. In the group receiving drug-eluting stents, 96% of the patients received either everolimus- or zotarolimus-eluting stents. The primary outcome was a composite of death from any cause and nonfatal spontaneous myocardial infarction after a median of 5 years of follow-up. Secondary outcomes included repeat revascularization, stent thrombosis, and quality of life. RESULTS At 6 years, the rates of the primary outcome were 16.6% in the group receiving drug-eluting stents and 17.1% in the group receiving bare-metal stents (hazard ratio, 0.98; 95% confidence interval [CI], 0.88 to 1.09; P=0.66). There were no significant between-group differences in the components of the primary outcome. The 6-year rates of any repeat revascularization were 16.5% in the group receiving drug-eluting stents and 19.8% in the group receiving bare-metal stents (hazard ratio, 0.76; 95% CI, 0.69 to 0.85; P<0.001); the rates of definite stent thrombosis were 0.8% and 1.2%, respectively (P=0.0498). Quality-of-life measures did not differ significantly between the two groups. CONCLUSIONS In patients undergoing PCI, there were no significant differences between those receiving drug-eluting stents and those receiving bare-metal stents in the composite outcome of death from any cause and nonfatal spontaneous myocardial infarction. Rates of repeat revascularization were lower in the group receiving drug-eluting stents. (Funded by the Norwegian Research Council and others; NORSTENT ClinicalTrials.gov number, NCT00811772 .).

Effect of intravenous TRO40303 as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: MITOCARE study results

AIM The MITOCARE study evaluated the efficacy and safety of TRO40303 for the reduction of reperfusion injury in patients undergoing revascularization for ST-elevation myocardial infarction (STEMI). METHODS Patients presenting with STEMI within 6 h of the onset of pain randomly received TRO40303 (n = 83) or placebo (n = 80) via i.v. bolus injection prior to balloon inflation during primary percutaneous coronary intervention in a double-blind manner. The primary endpoint was infarct size expressed as area under the curve (AUC) for creatine kinase (CK) and for troponin I (TnI) over 3 days. Secondary endpoints included measures of infarct size using cardiac magnetic resonance (CMR) and safety outcomes. RESULTS The median pain-to-balloon time was 180 min for both groups, and the median (mean) door-to-balloon time was 60 (38) min for all sites. Infarct size, as measured by CK and TnI AUCs at 3 days, was not significantly different between treatment groups. There were no significant differences in the CMR-assessed myocardial salvage index (1-infarct size/myocardium at risk) (mean 52 vs. 58% with placebo, P = 0.1000), mean CMR-assessed infarct size (21.9 g vs. 20.0 g, or 17 vs. 15% of LV-mass) or left ventricular ejection fraction (LVEF) (46 vs. 48%), or in the mean 30-day echocardiographic LVEF (51.5 vs. 52.2%) between TRO40303 and placebo. A greater number of adjudicated safety events occurred in the TRO40303 group for unexplained reasons. CONCLUSION This study in STEMI patients treated with contemporary mechanical revascularization principles did not show any effect of TRO40303 in limiting reperfusion injury of the ischaemic myocardium.

High Intensity Interval Training in Heart Failure Patients with Reduced Ejection Fraction

Background: Small studies have suggested that high-intensity interval training (HIIT) is superior to moderate continuous training (MCT) in reversing cardiac remodeling and increasing aerobic capacity in patients with heart failure with reduced ejection fraction. The present multicenter trial compared 12 weeks of supervised interventions of HIIT, MCT, or a recommendation of regular exercise (RRE). Methods: Two hundred sixty-one patients with left ventricular ejection fraction ⩽35% and New York Heart Association class II to III were randomly assigned to HIIT at 90% to 95% of maximal heart rate, MCT at 60% to 70% of maximal heart rate, or RRE. Thereafter, patients were encouraged to continue exercising on their own. Clinical assessments were performed at baseline, after the intervention, and at follow-up after 52 weeks. Primary end point was a between-group comparison of change in left ventricular end-diastolic diameter from baseline to 12 weeks. Results: Groups did not differ in age (median, 60 years), sex (19% women), ischemic pathogenesis (59%), or medication. Change in left ventricular end-diastolic diameter from baseline to 12 weeks was not different between HIIT and MCT (P=0.45); left ventricular end-diastolic diameter changes compared with RRE were −2.8 mm (−5.2 to −0.4 mm; P=0.02) in HIIT and −1.2 mm (−3.6 to 1.2 mm; P=0.34) in MCT. There was also no difference between HIIT and MCT in peak oxygen uptake (P=0.70), but both were superior to RRE. However, none of these changes was maintained at follow-up after 52 weeks. Serious adverse events were not statistically different during supervised intervention or at follow-up at 52 weeks (HIIT, 39%; MCT, 25%; RRE, 34%; P=0.16). Training records showed that 51% of patients exercised below prescribed target during supervised HIIT and 80% above target in MCT. Conclusions: HIIT was not superior to MCT in changing left ventricular remodeling or aerobic capacity, and its feasibility remains unresolved in patients with heart failure. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00917046.

Rationale and Design of the 'MITOCARE' Study: A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of TRO40303 for the Reduction of Reperfusion Injury in Patients Undergoing Percutaneous Coronary Intervention for Acute Myocardial Infarction

Treatment of acute ST-elevation myocardial infarction (STEMI) by reperfusion using percutaneous coronary intervention (PCI) or thrombolysis has provided clinical benefits; however, it also induces considerable cell death. This process is called reperfusion injury. The continuing high rates of mortality and heart failure after acute myocardial infarction (AMI) emphasize the need for improved strategies to limit reperfusion injury and improve clinical outcomes. The objective of this study is to assess safety and efficacy of TRO40303 in limiting reperfusion injury in patients treated for STEMI. TRO40303 targets the mitochondrial permeability transition pore, a promising target for the prevention of reperfusion injury. This multicenter, double-blind study will randomize patients with STEMI to TRO40303 or placebo administered just before balloon inflation or thromboaspiration during PCI. The primary outcome measure will be reduction in infarct size (assessed as plasma creatine kinase and troponin I area under the curve over 3 days). The main secondary endpoint will be infarct size normalized to the myocardium at risk (expressed by the myocardial salvage index assessed by cardiac magnetic resonance). The study is being financed under an EU-FP7 grant and conducted under the auspices of the MITOCARE research consortium, which includes experts from clinical and basic research centers, as well as commercial enterprises, throughout Europe. Results from this study will contribute to a better understanding of the complex pathophysiology underlying myocardial injury after STEMI. The present paper describes the rationale, design and the methods of the trial.Treatment of acute ST-elevation myocardial infarction (STEMI) by reperfusion using percutaneous coronary intervention (PCI) or thrombolysis has provided clinical benefits; however, it also induces considerable cell death. This process is called reperfusion injury. The continuing high rates of mortality and heart failure after acute myocardial infarction (AMI) emphasize the need for improved strategies to limit reperfusion injury and improve clinical outcomes. The objective of this study is to assess safety and efficacy of TRO40303 in limiting reperfusion injury in patients treated for STEMI. TRO40303 targets the mitochondrial permeability transition pore, a promising target for the prevention of reperfusion injury. This multicenter, double-blind study will randomize patients with STEMI to TRO40303 or placebo administered just before balloon inflation or thromboaspiration during PCI. The primary outcome measure will be reduction in infarct size (assessed as plasma creatine kinase and troponin I area under the curve over 3 days). The main secondary endpoint will be infarct size normalized to the myocardium at risk (expressed by the myocardial salvage index assessed by cardiac magnetic resonance). The study is being financed under an EU-FP7 grant and conducted under the auspices of the MITOCARE research consortium, which includes experts from clinical and basic research centers, as well as commercial enterprises, throughout Europe. Results from this study will contribute to a better understanding of the complex pathophysiology underlying myocardial injury after STEMI. The present paper describes the rationale, design and the methods of the trial. Copyright (c) 2012 S. Karger AG, Basel (Less)

BEtablocker Treatment After acute Myocardial Infarction in revascularized patients without reduced left ventricular ejection fraction (BETAMI): rationale and design of a prospective, randomized, open, blinded end-point study

Background Current guidelines on the use of &bgr;‐blockers in post–acute myocardial infarction (MI) patients without reduced left ventricular ejection fraction (LVEF) are based on studies before the implementation of modern reperfusion and secondary prevention therapies. It remains unknown whether &bgr;‐blockers will reduce mortality and recurrent MI in contemporary revascularized post‐MI patients without reduced LVEF. Design BETAMI is a prospective, randomized, open, blinded end point multicenter study in 10,000 MI patients designed to test the superiority of oral &bgr;‐blocker therapy compared to no &bgr;‐blocker therapy. Patients with LVEF ≥40% following treatment with percutaneous coronary intervention or thrombolysis and/or no clinical signs of heart failure are eligible to participate. The primary end point is a composite of all‐cause mortality or recurrent MI obtained from national registries over a mean follow‐up period of 3 years. Safety end points include rates of nonfatal MI, all‐cause mortality, ventricular arrhythmias, and hospitalizations for heart failure obtained from hospital medical records 30 days after randomization, and from national registries after 6 and 18 months. Key secondary end points include recurrent MI, heart failure, cardiovascular and all‐cause mortality, and clinical outcomes linked to &bgr;‐blocker therapy including drug adherence, adverse effects, cardiovascular risk factors, psychosocial factors, and health economy. Statistical analyses will be conducted according to the intention‐to‐treat principle. A prespecified per‐protocol analysis (patients truly on &bgr;‐blockers or not) will also be conducted. Conclusions The results from the BETAMI trial may have the potential of changing current clinical practice for treatment with &bgr;‐blockers following MI in patients without reduced LVEF. EudraCT number 2018–000590–75.

Infusion of TRO40303 in patients with ST-elevation myocardial infarction prior to primary percutaneous coronary intervention did not alter levels of inflammatory biomarkers in the MITOCARE study

Successful reperfusion is associated with lower levels of markers of myocardial damage and dysfunction in ST-elevation but not in non-ST-elevation myocardial infarction : insights from the PLATO trialBackground: Carbohydrate antigen 125 (CA125) is a mucin produced by serosal cells in response to mechanical and inflammatory stimuli. CA125 has emerged as prognostic biomarker in heart failure (HF) and correlates with markers of fluid overload, echocardiographic parameters and prognosis in HF patients. In patients with acute coronary syndrome (ACS), elevated CA125 is correlated with a higher risk of in-hospital HF. The relationship between CA125 and long-term prognosis in ACS patients has not previously been assessed. Purpose: The purpose of our study was to investigate if CA125 measured at the time of an acute coronary event is related to cardiac remodeling during the first year of follow-up and long-term risk for HF and death Methods: We measured CA125 in plasma within 24 hours of the acute event in 523 patients with acute myocardial infarction or unstable angina admitted to the Coronary Care Unit. Routine echocardiograms were performed in all participants. The primary outcomes were hospitalization with a diagnosis of heart failure or death during follow-up, identified through data from the Swedish Hospital Discharge Register and the Swedish Cause of Death Register. In a subgroup of 109 patients aged 75 years or above we assessed the relationships between baseline CA125 and echocardiographical parameters of cardiac structure and function at 1 year after the index ACS. Results: The median follow-up period was 27.3 months for incident HF and 39.5 months for mortality. In Cox proportional hazards models we found an adjusted hazard ratio of 1.51 (95% CI 1.08-2.12; p (Less)