Regression of Q waves and clinical outcomes following primary PCI in anterior STEMI.

BACKGROUND: Pathological Q waves are correlated with infarct size, and Q-wave regression is associated with left ventricular ejection fraction improvement. There are limited data regarding the association of Q-wave regression and clinical outcomes. Our main objective was to assess the association of pathological Q wave evolution after reperfusion with clinical outcomes after anterior STEMI. METHODS: Standard 12-lead electrocardiograms (ECGs) were recorded in 780 anterior STEMI patients treated with primary percutaneous coronary intervention (PCI) from the CIRCUS trial. ECGs were recorded before and 90 min following PCI, as well as at hospitalization discharge and 12 months of follow-up. The number of classic ECG criteria Q waves was scored for each ECG. Patients were classified in the Q wave regression group if they had regression of at least one Q wave between the post-PCI, the discharge and/or one year ECGs. Patients were classified in the Q wave persistent group if they had the same number or greater between the post-PCI, the discharge and/or 1 and one year ECGs. All-cause death and heart failure events were assessed for all patients at one year. RESULTS: There were 323(43%) patients with persistent Q waves (PQ group), 378(49%) patients with Q wave regression (RQ group) and 60(8%) patients with non-Q wave MI (NQ group). Infarct size as measured by the peak creatine kinase was significantly greater in the PQ group compared to the RQ and NQ groups (4633 ±â€¯2784 IU/l vs. 3814 ±â€¯2595 IU/l vs. 1733 ±â€¯1583 IU/l respectively, p < 0.0001). At one year, there were 22 deaths (7%) in the PQ-group, 15 (4%) in the RQ-group and none in the NQ-group (p = 0.04). There was a 4-fold increase in the risk of death or heart failure in the PQ compared to the NQ group (HR 4.7 [1.1; 19.3]; p = 0.03), but there was no significant difference between NQ and RQ groups (HR 3.3 [0.8; 13.8]; p = 0.09). CONCLUSION: In a population of anterior STEMI patients, persistent Q waves defined according to the classic ECG criteria after reperfusion was associated with a 4-fold increase in the risk of heart failure or death compared to non-Q-wave MI, while Q-wave regression was associated with significantly lower risk of events.

Importance of infarct size versus other variables for clinical outcomes after PPCI in STEMI patients.

Despite promising experimental studies and encouraging proof-of-concept clinical trials, interventions aimed at limiting infarct size have failed to improve clinical outcomes in patients with ST-elevation myocardial infarction (STEMI). Our objective was to examine whether variables (cardiovascular risk factors, comorbidities, post-procedural variables, cotreatments) might be associated with clinical outcomes in STEMI patients independently from infarct size reduction. The present study was based on a post hoc analysis of the CIRCUS trial database (Clinicaltrials.gov NCT01502774) that assessed the clinical benefit of a single intravenous bolus of cyclosporine in 969 patients with anterior STEMI. Since cyclosporine had no detectable effect on clinical outcomes as well as on any measured variable, we here considered the whole study population as one group. Multivariate analysis was performed to address the respective weight of infarct size and variables in clinical outcomes. Multivariate analysis revealed that several variables (including gender, hypertension, renal dysfunction, TIMI flow grade post-PCI < 3, and treatment administered after PCI with betablockers and angiotensin-converting enzyme inhibitors) had per se a significant influence on the occurrence of [death or hospitalization for heart failure] at 1 year. The relative weight of infarct size and variables on the composite endpoint of [death or hospitalization for heart failure] at 1 year was 18% and 82%, respectively. Several variables contribute strongly to the clinical outcomes of STEMI patients suggesting that cardioprotective strategy might not only focus on infarct size reduction.

Cyclosporine before PCI in Patients with Acute Myocardial Infarction.

BACKGROUND: Experimental and clinical evidence suggests that cyclosporine may attenuate reperfusion injury and reduce myocardial infarct size. We aimed to test whether cyclosporine would improve clinical outcomes and prevent adverse left ventricular remodeling. METHODS: In a multicenter, double-blind, randomized trial, we assigned 970 patients with an acute anterior ST-segment elevation myocardial infarction (STEMI) who were undergoing percutaneous coronary intervention (PCI) within 12 hours after symptom onset and who had complete occlusion of the culprit coronary artery to receive a bolus injection of cyclosporine (administered intravenously at a dose of 2.5 mg per kilogram of body weight) or matching placebo before coronary recanalization. The primary outcome was a composite of death from any cause, worsening of heart failure during the initial hospitalization, rehospitalization for heart failure, or adverse left ventricular remodeling at 1 year. Adverse left ventricular remodeling was defined as an increase of 15% or more in the left ventricular end-diastolic volume. RESULTS: A total of 395 patients in the cyclosporine group and 396 in the placebo group received the assigned study drug and had data that could be evaluated for the primary outcome at 1 year. The rate of the primary outcome was 59.0% in the cyclosporine group and 58.1% in the control group (odds ratio, 1.04; 95% confidence interval [CI], 0.78 to 1.39; P=0.77). Cyclosporine did not reduce the incidence of the separate clinical components of the primary outcome or other events, including recurrent infarction, unstable angina, and stroke. No significant difference in the safety profile was observed between the two treatment groups. CONCLUSIONS: In patients with anterior STEMI who had been referred for primary PCI, intravenous cyclosporine did not result in better clinical outcomes than those with placebo and did not prevent adverse left ventricular remodeling at 1 year. (Funded by the French Ministry of Health and NeuroVive Pharmaceutical; CIRCUS ClinicalTrials.gov number, NCT01502774; EudraCT number, 2009-013713-99.).

Rationale and design of the Cyclosporine to ImpRove Clinical oUtcome in ST-elevation myocardial infarction patients (the CIRCUS trial).

BACKGROUND: Both acute myocardial ischemia and reperfusion contribute to cardiomyocyte death in ST-elevation myocardial infarction (STEMI). The final infarct size is the principal determinant of subsequent clinical outcome in STEMI patients. In a proof-of-concept phase II trial, the administration of cyclosporine prior to primary percutaneous coronary intervention (PPCI) has been associated with a reduction of infarct size in STEMI patients. METHODS: CIRCUS is an international, prospective, multicenter, randomized, double-blinded, placebo-controlled trial. The study is designed to compare the efficacy and safety of cyclosporine versus placebo, in addition to revascularization by PPCI, in patients presenting with acute anterior myocardial infarction within 12 hours of symptoms onset and initial TIMI flow ≤1 in the culprit left anterior descending coronary artery. Patients are randomized in a 1:1 fashion to 2.5 mg/kg intravenous infusion of cyclosporine or matching placebo performed in the minutes preceding PCI. The primary efficacy end point of CIRCUS is a composite of 1-year all-cause mortality, rehospitalization for heart failure or heart failure worsening during initial hospitalization, and left ventricular adverse remodeling as determined by sequential transthoracic echochardiography. Secondary outcomes will be tested using a hierarchical sequence of left ventricular (LV) ejection fraction and absolute measurements of LV volumes. The composite of death and rehospitalization for heart failure or heart failure worsening during initial hospitalization will be further assessed at three years after the initial infarction. RESULTS: Recruitment lasted from April 2011 to February 2014. The CIRCUS trial has recruited 975 patients with acute anterior myocardial infarction. The 12-months results are expected to be available in 2015. CONCLUSIONS: The CIRCUS trial is testing the hypothesis that cyclosporine in addition to early revascularization with PPCI compared to placebo in patients with acute anterior myocardial infarction reduces the incidence of death, heart failure and adverse LV remodeling at one-year follow-up.

[Public clinical trials: which kind of monitoring should be used?]. / Essais cliniques institutionnels : quel monitoring ?

OBJECTIVE: Sponsors must take responsibility for the quality of trials at the best possible cost. Our objective was to describe the most frequent quality failures, how they impact trial results, and identify the most efficient monitoring strategies using published articles and reports. RESULTS: Errors affecting clinical trials include conception, procedures, data management, and data analysis. The consequences are usually an overestimation of the treatment effect. No study shows that monitoring reduces the risk of errors, and there is no comparison of monitoring methods. Many research organisations advocate for monitoring based on risk analysis and recommend an extensive use of centralised monitoring. CONCLUSIONS: Trial quality depends on trial conception and design. Study conduct should guarantee a maximum level of quality level. This should be done using risk management and extensive centralised monitoring.

Life-threatening arrhythmias in anterior ST-segment elevation myocardial infarction patients treated by percutaneous coronary intervention: adverse impact of morphine.

AIMS: Important controversies remain concerning the determinants of life-threatening arrhythmias during ST-segment elevation myocardial infarction (STEMI) and their impact on late adverse events. This study sought to investigate which factors might facilitate ventricular tachycardia (VT) and ventricular fibrillation (VF), in a homogeneous population of anterior STEMI patients defined by abrupt left anterior descending coronary artery (LAD) occlusion and no collateral flow. METHODS AND RESULTS: The 967 patients, who entered into the CIRCUS (Does Cyclosporine ImpRove Clinical oUtcome in ST elevation myocardial infarction patients) study, were assessed for further analysis. Acute VT/VF was defined as VT (run of tachycardia >30 s either self-terminated or requiring electrical/pharmacological cardioversion) or VF documented by electrocardiogram or cardiac monitoring, during transportation to the cathlab or initial hospitalization. VT/VF was documented in 136 patients (14.1%). Patients with VT/VF were younger and had shorter time from symptom onset to hospital arrival. Site of LAD occlusion, thrombus burden, area at risk, pre-percutaneous coronary intervention Thrombolysis in Myocardial Infarction flow, and ST-segment resolution were similar to that of patients without VT/VF. There was no impact of VT/VF on left ventricular remodelling or clinical outcomes. By multivariate analysis, the use of morphine (odds ratio 1.71; 95% confidence interval (1.13-2.60); P = 0.012) was the sole independent predictor of VT/VF occurrence. CONCLUSIONS: In STEMI patients with LAD occlusion, our findings support the view that morphine could favour severe ventricular arrhythmias.

Predictive value of early cardiac magnetic resonance imaging functional and geometric indexes for adverse left ventricular remodelling in patients with anterior ST-segment elevation myocardial infarction: A report from the CIRCUS study.

BACKGROUND: Postinfarction adverse left ventricular (LV) remodelling is strongly associated with heart failure events. Conicity index, sphericity index and LV global functional index (LVGFI) are new LV remodelling indexes assessed by cardiac magnetic resonance (CMR). AIM: To assess the predictive value of the new indexes for 1-year adverse LV remodelling in patients with anterior ST-segment elevated myocardial infarction (STEMI). METHODS: CMR studies were performed in 129 patients with anterior STEMI (58±12 years; 78% men) from the randomized CIRCUS trial (CMR substudy) treated with primary percutaneous coronary intervention and followed for the occurrence of major adverse cardiovascular events (MACE) (death or hospitalization for heart failure). Conicity index, sphericity index, LVGFI, infarct size and microvascular obstruction (MVO) were assessed by CMR performed 5±4 days after coronary reperfusion. Adverse LV remodelling was defined as an increase in LV end-diastolic volume of ≥15% by transthoracic echocardiography at 1 year. RESULTS: Adverse LV remodelling occurred in 27% of patients at 1 year. Infarct size and MVO were significantly predictive of adverse LV remodelling: odds ratio [OR] 1.03, 95% confidence interval [CI] 1.01-1.05 (P<0.001) and OR 1.12, 95% CI 1.05-1.22 (P<0.001), respectively. Among the newly tested indexes, only LVGFI was significantly predictive of adverse LV remodelling (OR 1.10, 95% CI 1.03-1.16; P=0.001). In multivariable analysis, infarct size remained an independent predictor of adverse LV remodelling at 1 year (OR 1.05, 95% CI 1.02-1.08; P<0.001). LVGFI and infarct size were associated with occurrence of MACE: OR 1.21, 95% CI 1.08-1.37 (P<0.001) and OR 1.02, 95% CI 1.00-1.04 (P=0.018), respectively. Conicity and sphericity indexes were not associated with MACE. CONCLUSIONS: LVGFI was associated with adverse LV remodelling and MACE 1 year after anterior STEMI.

Neprilysin levels at the acute phase of ST-elevation myocardial infarction.

BACKGROUND: Several preliminary analyses suggested an association between neprilysin (NEP) levels and myocardial infarction. HYPOTHESIS: The objective was to assess whether NEP plasma levels following reperfusion might be a surrogate for infarct size (IS) or predict adverse outcomes in acute ST-segment elevation myocardial infarction (STEMI) patients. METHODS: We measured NEP levels in a prospective cohort of 203 patients with STEMI referred for primary percutaneous coronary intervention. Circulating soluble NEP was measured by enzyme-linked immunosorbent assay at admission (t0) and 4 hours later (t4) following reperfusion and on 7 times points (t0, t4, t12, t24, t48, day 7 and day 30) in a subset of 21 patients. IS and left ventricular ejection fraction (LVEF) were measured at 1 month by cardiac magnetic resonance. Adverse cardiovascular outcomes were collected at 12-month follow-up. RESULTS: Median t0 and t4 NEP levels in 203 patients were respectively 88.3 pg/mL (interquartile range [IQR] [14; 375.4]) and 101.5 pg/mL (IQR [18.5; 423.8]). These levels remained unchanged over 1 month (P = 0.70). NEP levels did not correlate significantly with IS (P = 0.51) or LVEF (P = 0.34). There was no correlation between NEP and troponin, creatine kinase and interleukin-6 levels at h0 and h4. NEP levels above the median were not associated with adverse outcomes at follow-up (hazard ratio = 1.28, 95% confidence interval [0.69; 2.37]; P = 0.42). CONCLUSIONS: NEP serum levels were widely distributed and did not change significantly in the first hours and 1-month period following reperfusion in STEMI patients. There was no significant relationship with markers of infarct size and inflammation, and 1-year adverse outcomes.

Effect and Safety of Morphine Use in Acute Anterior ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Morphine is commonly used to treat chest pain during myocardial infarction, but its effect on cardiovascular outcome has never been directly evaluated. The aim of this study was to examine the effect and safety of morphine in patients with acute anterior ST-segment elevation myocardial infarction followed up for 1 year. METHODS AND RESULTS: We used the database of the CIRCUS (Does Cyclosporine Improve Outcome in ST Elevation Myocardial Infarction Patients) trial, which included 969 patients with anterior ST-segment elevation myocardial infarction, admitted for primary percutaneous coronary intervention. Two groups were defined according to use of morphine preceding coronary angiography. The composite primary outcome was the combined incidence of major adverse cardiovascular events, including cardiovascular death, heart failure, cardiogenic shock, myocardial infarction, unstable angina, and stroke during 1 year. A total of 554 (57.1%) patients received morphine at first medical contact. Both groups, with and without morphine treatment, were comparable with respect to demographic and periprocedural characteristics. There was no significant difference in major adverse cardiovascular events between patients who received morphine compared with those who did not (26.2% versus 22.0%, respectively; P=0.15). The all-cause mortality was 5.3% in the morphine group versus 5.8% in the no-morphine group (P=0.89). There was no difference between groups in infarct size as assessed by the creatine kinase peak after primary percutaneous coronary intervention (4023±118 versus 3903±149 IU/L; P=0.52). CONCLUSIONS: In anterior ST-segment elevation myocardial infarction patients treated by primary percutaneous coronary intervention, morphine was used in half of patients during initial management and was not associated with a significant increase in major adverse cardiovascular events at 1 year.

Effect of Cyclosporine in Nonshockable Out-of-Hospital Cardiac Arrest: The CYRUS Randomized Clinical Trial.

IMPORTANCE: Experimental evidence suggests that cyclosporine prevents postcardiac arrest syndrome by attenuating the systemic ischemia reperfusion response. OBJECTIVE: To determine whether early administration of cyclosporine at the time of resuscitation in patients with out-of-hospital cardiac arrest (OHCA) would prevent multiple organ failure. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, single-blind, randomized clinical trial was conducted from June 22, 2010, to March 13, 2013 (Cyclosporine A in Out-of-Hospital Cardiac Arrest Resuscitation [CYRUS]). Sixteen intensive care units in 7 university-affiliated hospitals and 9 general hospitals in France participated. A total of 6758 patients who experienced nonshockable OHCA (ie, asystole or pulseless electrical activity) were assessed for eligibility. Analyses were performed according to the intention-to-treat analysis. INTERVENTIONS: Patients received an intravenous bolus injection of cyclosporine, 2.5 mg/kg, at the onset of advanced cardiovascular life support (cyclosporine group) or no additional intervention (control group). MAIN OUTCOMES AND MEASURES: The primary end point was the Sequential Organ Failure Assessment (SOFA) score, assessed 24 hours after hospital admission, which ranges from 0 to 24 (with higher scores indicating more severe organ failure). Secondary end points included survival at 24 hours, hospital discharge, and favorable neurologic outcome at discharge. RESULTS: Of the 6758 patients screened, 794 were included in intention-to-treat analysis (cyclosporine, 400; control, 394). The median (interquartile range [IQR]) ages were 63.0 (54.0-71.8) years for the cyclosporine group and 66.0 (57.0-74.0) years for the control group. The cohorts included 293 men (73.3%) in the treatment group and 288 men (73.1%) in the control group. At 24 hours after hospital admission, the SOFA score was not significantly different between the cyclosporine (median, 10.0; IQR, 7.0-13.0) and the control (median, 11.0; IQR, 7.0-15.0) groups. Survival was not significantly different between the 98 (24.5%) cyclosporine vs 101 (25.6%) control patients at hospital admission (adjusted odds ratio [aOR], 0.94; 95% CI, 0.66-1.34), at 24 hours for 67 (16.8%) vs 62 (15.7%) patients (aOR, 1.08; 95% CI, 0.71-1.63), and at hospital discharge for 10 (2.5%) vs 5 (1.3%) patients (aOR, 2.00; 95% CI, 0.61-6.52). Favorable neurologic outcome at discharge was comparable between the cyclosporine and control groups: 7 (1.8%) vs 5 (1.3%) patients (aOR, 1.39; 95% CI, 0.39-4.91). CONCLUSION AND RELEVANCE: In patients presenting with nonshockable cardiac rhythm after OHCA, cyclosporine does not prevent early multiple organ failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01595958; EudraCT Identifier: 2009-015725-37.