Clevidipine as a therapeutic and cost-effective alternative to sodium nitroprusside in patients with acute aortic syndromes.

BACKGROUND: Sodium nitroprusside is the preferred agent for the treatment of high blood pressure during acute aortic syndrome if blood pressure remains elevated after heart rate control with beta-blockers. The increasing cost of sodium nitroprusside in the USA led us to assess the efficacy and safety of intravenous clevidipine, a calcium channel blocker with quick onset of action, short half-life and significantly lower costs than sodium nitroprusside, in patients presenting with acute aortic syndrome. METHODS: We performed a retrospective chart review of consecutive patients admitted to the Cleveland Clinic Cardiac Intensive Care Unit from 2013-2016 with a diagnosis of acute aortic syndrome. Patients who received intravenous sodium nitroprusside were compared with those receiving intravenous clevidipine. The primary outcome was a significant difference in blood pressure at one, three and six hours. Secondary outcomes included time to achieving blood pressure target and in hospital mortality with rates of hypotension and bradycardia as safety endpoints. RESULTS: A total of 85 patients with suspected acute aortic pathology received clevidipine and 50 received sodium nitroprusside. Clinical and demographic characteristics were similar in both groups, except for a higher incidence of abdominal aortic aneurysm in the clevidipine group and for a trend towards higher use of labetalol in the clevidipine group. There were no significant differences in blood pressure or heart rate at one, three and six hours after starting either infusion. The rates of hypotension, bradycardia and in-hospital mortality did not differ. Time to achieve blood pressure control were also similar between groups. CONCLUSION: Intravenous clevidipine appears to be a safe and effective alternative to sodium nitroprusside for the management of high blood pressure during acute aortic dissection. In the USA, clevidipine could represent a cost effective therapy providing similar outcomes than sodium nitroprusside.

Data on administration of cyclosporine, nicorandil, metoprolol on reperfusion related outcomes in ST-segment Elevation Myocardial Infarction treated with percutaneous coronary intervention.

Mortality and morbidity in patients with ST elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) are still high [1]. A huge amount of the myocardial damage is related to the mitochondrial events happening during reperfusion [2]. Several drugs directly and indirectly targeting mitochondria have been administered at the time of the PCI and their effect on fatal (all-cause mortality, cardiovascular (CV) death) and non fatal (hospital readmission for heart failure (HF)) outcomes have been tested showing conflicting results [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. Data from 15 trials have been pooled with the aim to analyze the effect of drug administration versus placebo on outcome [17]. Subgroup analysis are here analyzed: considering only randomized clinical trial (RCT) on cyclosporine or nicorandil [3], [4], [5], [9], [10], [11], excluding a trial on metoprolol [12] and comparing trial with follow-up length <12 months versus those with longer follow-up [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. This article describes data related article titled "Clinical Benefit of Drugs Targeting Mitochondrial Function as an Adjunct to Reperfusion in ST-segment Elevation Myocardial Infarction: a Meta-Analysis of Randomized Clinical Trials" [17].

Safety and Efficacy of Bivalirudin in Patients With Diabetes Mellitus Undergoing Percutaneous Coronary Intervention: From the REPLACE-2, ACUITY and HORIZONS-AMI Trials.

Optimal antithrombotic pharmacotherapy in patients affected by diabetes mellitus (DM) undergoing percutaneous coronary intervention is unclear. We sought to evaluate the safety and efficacy of bivalirudin compared with heparin plus a glycoprotein IIb/IIIa inhibitor (GPI) in patients with DM undergoing percutaneous coronary intervention. We pooled patient-level data from the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events-2, Acute Catheterization and Urgent Intervention Triage strategy, and Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction trials. The primary efficacy end point was the incidence of major adverse cardiac events, defined as the composite of death, myocardial infarction, or unplanned revascularization at 30 days. The primary safety end point was the incidence of 30-day non-coronary artery bypass graft-related major bleeding. All-cause mortality was reported at 30 days and 1 year. Of the 14,737 patients included in the pooled database, 3,641 (24.7%) had DM. Patients with DM had higher rates of 30-day major bleeding and 30-day and 1-year all-cause mortality. There were no differences in 30-day major adverse cardiac events between bivalirudin versus heparin plus GPI in patients with DM (6.9% vs 7.8%; relative risk [RR] 0.89, 95% CI 0.71 to 1.12) or without DM (7.5% vs 6.7%; RR 1.11, 95% CI 0.97 to 1.27; pinteraction = 0.10). Bivalirudin treatment was associated with reduced risk of major bleeding in similar magnitude in patients with DM (4.3% vs 6.6% RR 0.68, 95% CI 0.51 to 0.89) or without DM (3.2% vs 6.1%; RR 0.51, 95% CI 0.43 to 0.61; pinteraction = 0.15). The hemorrhagic benefit of bivalirudin was noted for both access site- and non-access site-related bleeding. Overall, bivalirudin treatment was associated with a significant 1-year mortality benefit (2.7% vs 3.3%; RR 0.82, 95% CI 0.68 to 0.98; p = 0.03), which was consistent between patients with or without DM (pinteraction = 0.30). In conclusion, compared with heparin plus GPI, bivalirudin was associated with similar 30-day antithrombotic efficacy and better 30-day freedom from bleeding and 1-year mortality, irrespective of diabetic status.

Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): a randomised clinical trial

BACKGROUND: REG1 is a novel anticoagulation system consisting of pegnivacogin, an RNA aptamer inhibitor of coagulation factor IXa, and anivamersen, a complementary sequence reversal oligonucleotide. We tested the hypothesis that near complete inhibition of factor IXa with pegnivacogin during percutaneous coronary intervention, followed by partial reversal with anivamersen, would reduce ischaemic events compared with bivalirudin, without increasing bleeding. METHODS: We did a randomised, open-label, active-controlled, multicentre, superiority trial to compare REG1 with bivalirudin at 225 hospitals in North America and Europe. We planned to randomly allocate 13,200 patients undergoing percutaneous coronary intervention in a 1:1 ratio to either REG1 (pegnivacogin 1 mg/kg bolus [>99% factor IXa inhibition] followed by 80% reversal with anivamersen after percutaneous coronary intervention) or bivalirudin. Exclusion criteria included ST segment elevation myocardial infarction within 48 h. The primary efficacy endpoint was the composite of all-cause death, myocardial infarction, stroke, and unplanned target lesion revascularisation by day 3 after randomisation. The principal safety endpoint was major bleeding. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, identifier NCT01848106. The trial was terminated early after enrolment of 3232 patients due to severe allergic reactions...

Utility of CMR Markers of Myocardial Injury in Predicting LV Functional Recovery: Results from PROTECTION AMI CMR Sub-study.

BACKGROUND: Adverse left ventricular (LV) remodelling following acute ST-segment elevation myocardial infarction (STEMI) has prognostic importance. We aimed to predict 90-day left ventricular (LV) function following acute STEMI using variables from clinical presentation, biomarkers, and cardiovascular magnetic resonance imaging (CMR). METHODS: Consecutive patients undergoing primary percutaneous coronary intervention for anterior STEMI as part of the Selective Inhibition of Delta-protein Kinase C for the Reduction of Infarct Size in Acute Myocardial Infarction (PROTECTION-AMI) trial were enrolled into the CMR sub-study at selected sites. CMR was performed at baseline (days 3 to 5) and 90 days and used to evaluate infarct size, myocardial salvage index, infarct heterogeneity, microvascular obstruction and global LV function. Biochemical markers including creatinine kinase area under the curve (CK AUC), peak CK, peak CK-myocardial band (CK-MB) and AUC, and troponin I were collected at specific time-points. RESULTS: Ninety-six patients were enrolled in the CMR sub study and 85 completed the 90-day follow-up, across 24 centres worldwide. LV ejection fraction (EF) was 56% (46-63%) at baseline and 60% (49-67%) at 90 days (p<0.001). Infarct size had moderate inverse correlation with 90-day EF (Spearman's rho=-0.7, p < 0.001) and had the strongest correlation when compared to myocardial salvage index (Spearman's rho=0.5, p=0.001), infarct heterogeneity (Spearman's rho=-0.4, p=0.02 or microvascular obstruction (Spearman's rho=-0.4, p<0.001). All biochemical markers had similar moderate relationship to LVEF at 90 days (Spearman's rho -0.6 to -0.8, p=0.001). In a multivariable model, only baseline LVEF, CMR infarct size and infarct heterogeneity independently predicted 90-day LVEF. CONCLUSION: This study reports findings of a combined CMR protocol (including myocardial oedema imaging) in a multi-centre, multi-vendor setting. We found infarct size, infarct heterogeneity and myocardial salvage index correlated favourably with 90-day LVEF, however only the former two were independently predictive.

Choice of arterial access site and outcomes in patients with acute coronary syndromes managed with an early invasive strategy: the ACUITY trial.

AIMS: The purpose of this study was to evaluate the impact of arterial access site on bleeding and ischaemic outcomes, overall and by treatment strategy, in patients with acute coronary syndromes (ACS). METHODS AND RESULTS: In the ACUITY trial, 13,819 patients with moderate and high-risk ACS were randomised to either heparin (unfractionated or enoxaparin) plus a glycoprotein IIb/IIIa inhibitor (GPI), bivalirudin plus a GPI, or bivalirudin alone. Per operator choice, femoral access was utilised in 11,989 patients (93.8%) and radial access in 798 patients (6.2%). There was no significant difference in composite ischaemia between the radial and femoral approaches at 30 days (8.1% vs 7.5%, p=0.18) or 1 year (14.7% vs 15.5%, p=0.77), although fewer major bleeding complications occurred with the use of radial access (3.0%vs4.8%, p=0.03). Use of bivalirudin monotherapy was associated with significantly less 30-day major bleeding than heparin plus GPI after femoral access (3.0% vs 5.8%, p<0.0001), but not with radial access (4.2% vs 2.2%, P=0.19). Major or minor organ bleeding was reduced with bivalirudin monotherapy compared to heparin plus GPI to a similar extent with both femoral (4.1% vs 7.4%, P<0.0001) and radial (4.9% vs 7.2%, P=0.26) access. CONCLUSIONS: Transradial compared to femoral arterial access is associated with similar rates of composite ischaemia and with fewer major bleeding complications in patients with ACS managed invasively. Bivalirudin monotherapy compared to heparin plus GPIs significantly reduces access site related major bleeding complications with femoral but not radial artery access, though non-access site related bleeding is reduced by bivalirudin monotherapy in all patients.

Bivalirudin provides rapid, effective, and reliable anticoagulation during off-pump coronary revascularization: results of the "EVOLUTION OFF" trial.

In the EVOLUTION OFF trial, we evaluated the safety and efficacy of bivalirudin during off-pump coronary artery bypass grafting as compared with heparin-protamine. In this subanalysis of EVOLUTION OFF data of bivalirudin-treated patients, we assessed the pharmacokinetics (PK) and effectiveness of bivalirudin anticoagulation to achieve target activated clotting time (ACT)+ values. Data from 101 patients were assessed. A bolus of 0.75 mg/kg of bivalirudin was followed by a continuous infusion of 1.75 mg x kg(-1) x h(-1) during the grafting procedure. An ACT+ value of >300 s was the target. In four patients, PK data for bivalirudin were obtained. Only in exceptional cases were repeat fractional boluses or an increase of the infusion rate required. Assessment of the PK data showed a mean concentration of bivalirudin after the initial bolus of 11.0 +/- 0.53 microg/mL and a mean concentration during infusion of 11.2 +/- 2.32 microg/mL. Pearson's correlation between bivalirudin concentrations and ACT+ values was 0.92. Bivalirudin PK data consistently exceeded concentrations of 6.5 microg/mL, which have been evaluated as effective during percutaneous coronary intervention. The correlation between bivalirudin levels and ACT+ values was good, and the target ACT+ values were almost always achieved. These results suggest that bivalirudin, given according to the current protocol, provides reliable and effective anticoagulation during off-pump coronary artery bypass graft surgery.