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.

Long-term prognostic value of residual pulmonary vascular obstruction at discharge in patients with intermediate- to high-risk pulmonary embolism.

BACKGROUND: We evaluated prognostic value at 6 months of residual pulmonary vascular obstruction (RPVO) measured before discharge in patients with intermediate- or high-risk pulmonary embolism (PE). METHODS AND RESULTS: Prospective registry including 416 consecutive patients with intermediate- or high-risk PE who survived the acute phase. Patients with previous cardiopulmonary disease were excluded. Perfusion lung scans were performed within 6-8 days after the onset of treatment. Residual pulmonary vascular obstruction was graded as the proportion of the lung not perfused. Primary objective was a combined endpoint at 6 months, including death, recurrent PE, and appearance of signs of heart failure. At 6 months, 32 patients (7.7%) had at least one adverse event: 12 deaths (2.9%), 12 recurrent PE (2.9%), and 14 (3.4%) heart failure. Independent predictors of combined endpoint were: cancer [odds ratio (OR) 3.07 (1.22-7.85)]; renal insufficiency at admission [OR: 2.53 (1.17-5.8)]; persistent signs of right ventricular dysfunction at 48 h echography [OR: 3.99 (1.36-11.3)]. The severity of RPVO at discharge was significantly associated with an unfavourable outcome [OR: 2.66 (1.58-3.93)]. The incremental prognostic value of RPVO information was confirmed by significantly improved goodness-of-fit. Threshold RPVO for predicting adverse events was estimated at 35% [area under the curve = 0.76 (0.73-0.82)]. Patients with RPVO greater than threshold at discharge had a significantly higher risk of death at 6 months (P = 0.01). CONCLUSIONS: Residual pulmonary vascular obstruction evaluated before hospital discharge in patients with intermediate- to high-risk PE is a powerful prognostic factor for a 6-month outcome. RPVO ≥35% is associated with an increased risk of adverse events at 6 months.