Adam Greenbaum

Intravenous Erythropoietin in Patients With ST-Segment Elevation Myocardial Infarction: REVEAL: A Randomized Controlled Trial

CONTEXT Acute ST-segment elevation myocardial infarction (STEMI) is a leading cause of morbidity and mortality. In experimental models of MI, erythropoietin reduces infarct size and improves left ventricular (LV) function. OBJECTIVE To evaluate the safety and efficacy of a single intravenous bolus of epoetin alfa in patients with STEMI. DESIGN, SETTING, AND PATIENTS A prospective, randomized, double-blind, placebo-controlled trial with a dose-escalation safety phase and a single dose (60,000 U of epoetin alfa) efficacy phase; the Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) trial was conducted at 28 US sites between October 2006 and February 2010, and included 222 patients with STEMI who underwent successful percutaneous coronary intervention (PCI) as a primary or rescue reperfusion strategy. INTERVENTION Participants were randomly assigned to treatment with intravenous epoetin alfa or matching saline placebo administered within 4 hours of reperfusion. MAIN OUTCOME MEASURE Infarct size, expressed as percentage of LV mass, assessed by cardiac magnetic resonance (CMR) imaging performed 2 to 6 days after study medication administration (first CMR) and again 12 ± 2 weeks later (second CMR). RESULTS In the efficacy cohort, the infarct size did not differ between groups on either the first CMR scan (n = 136; 15.8% LV mass [95% confidence interval {CI}, 13.3-18.2% LV mass] for the epoetin alfa group vs 15.0% LV mass [95% CI, 12.6-17.3% LV mass] for the placebo group; P = .67) or on the second CMR scan (n = 124; 10.6% LV mass [95% CI, 8.4-12.8% LV mass] vs 10.4% LV mass [95% CI, 8.5-12.3% LV mass], respectively; P = .89). In a prespecified analysis of patients aged 70 years or older (n = 21), the mean infarct size within the first week (first CMR) was larger in the epoetin alfa group (19.9% LV mass; 95% CI, 14.0-25.7% LV mass) than in the placebo group (11.7% LV mass; 95% CI, 7.2-16.1% LV mass) (P = .03). In the safety cohort, of the 125 patients who received epoetin alfa, the composite outcome of death, MI, stroke, or stent thrombosis occurred in 5 (4.0%; 95% CI, 1.31%-9.09%) but in none of the 97 who received placebo (P = .04). CONCLUSIONS In patients with STEMI who had successful reperfusion with primary or rescue PCI, a single intravenous bolus of epoetin alfa within 4 hours of PCI did not reduce infarct size and was associated with higher rates of adverse cardiovascular events. Subgroup analyses raised concerns about an increase in infarct size among older patients. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00378352.

Renal function-based contrast dosing to define safe limits of radiographic contrast media in patients undergoing percutaneous coronary interventions.

OBJECTIVES The aim of this study was to evaluate the association between calculated creatinine clearance (CCC)-based contrast dose and renal complications in patients undergoing percutaneous coronary interventions (PCI). BACKGROUND Excess volumes of contrast media are associated with renal complications in patients undergoing cardiac procedures. Because contrast media are excreted by the kidney, we hypothesized that a dose estimation on the basis of CCC would provide a simple strategy to define a safe dose of contrast media. METHODS We assessed the association between CCC-based contrast dose and the risk of contrast-induced nephropathy (CIN) and need for in-hospital dialysis in 58,957 patients undergoing PCI and enrolled in the BMC2 (Blue Cross Blue Shield of Michigan Cardiovascular Consortium) registry from 2007 to 2008. Patients receiving dialysis at the time of the procedure were excluded. RESULTS The risk of CIN and nephropathy requiring dialysis (NRD) was directly associated with increasing contrast volume adjusted for renal function. The risk for CIN and NRD approached significance when the ratio of contrast dose/CCC exceeded 2 (adjusted odds ratio [OR] for CIN: 1.16, 95% confidence interval [CI]: 0.98 to 1.37, adjusted OR for NRD: 1.72, 95% CI: 0.9 to 3.27) and was dramatically elevated in patients exceeding a contrast to CCC ratio of 3 (adjusted OR for CIN: 1.46, 95% CI: 1.27 to 1.66, adjusted OR for NRD: 1.89, 95% CI: 1.21 to 2.94). CONCLUSIONS Our study supports the need for minimizing contrast dose in patients with renal dysfunction. A contrast dose on the basis of estimated renal function with a planned contrast volume restricted to less than thrice and preferably twice the CCC might be valuable in reducing the risk of CIN and NRD.

Adventitial Delivery of an Allogeneic Bone Marrow–Derived Adherent Stem Cell in Acute Myocardial Infarction Phase I Clinical Study

Rationale: MultiStem is an allogeneic bone marrow–derived adherent adult stem cell product that has shown efficacy in preclinical models of acute myocardial infarction (AMI). In this phase I clinical trial in patients with first ST-elevation–myocardial infarction (STEMI), we combine first-in-man delivery of MultiStem with a first-in-coronary adventitial delivery system to determine the effects of this system on left ventricular function at 4 months after AMI. Objective: Test the effects of adventitial delivery of Multistem in the peri-infarct period in patients with first STEMI. Methods and Results: This study was a phase I, open-label, dose-escalating registry control group study. Nineteen patients received MultiStem (20 million, n=6; 50 million, n=7; or 100 million, n=6) and 6 subjects were assigned to the registry control group. Two to 5 days after AMI, we delivered MultiStem to the adventitia of the infarct-related vessel in patients with first-time STEMI. All patients underwent primary percutaneous coronary intervention with resulting Thrombolysis In Myocardial Infarction grade 3 flow and with ejection fraction (EF) ⩽45% as determined by echocardiogram or left ventriculogram within 12 hours of primary percutaneous coronary intervention. The cell product (20 million, 50 million, or 100 million) was well tolerated, and no serious adverse events were deemed related to MultiStem. There was no increase in creatine kinase-MB or troponin associated with the adventitial delivery of MultiStem. In patients with EF determined to be ⩽45% by a core laboratory within 24 hours before the MultiStem injection, we observed a 0.9 (n=4), 3.9 (n=4), 13.5 (n=5), and 10.9 (n=2) percent absolute increases in EF in the registry, 20 million, 50 million, and 100 million dose groups, respectively. The increases in EF in the 50 million and 100 million groups were accompanied by 25.4 and 8.4 mL increases in left ventricular stroke volume. Conclusions: In this study, the delivery of MultiStem to the myocardium in patients with recent STEMI was well tolerated and safe. In patients who exhibited significant myocardial damage, the delivery of ≥50 million MultiStem resulted in improved EF and stroke volume 4 months later. These findings support further development of MultiStem in patients with AMI and they validate the potential of a system for delivery of adult stem cells at any time after primary percutaneous coronary intervention.

Caval-aortic access to allow transcatheter aortic valve replacement in otherwise ineligible patients: initial human experience.

OBJECTIVES This study describes the first use of caval-aortic access and closure to enable transcatheter aortic valve replacement (TAVR) in patients who lacked other access options. Caval-aortic access refers to percutaneous entry into the abdominal aorta from the femoral vein through the adjoining inferior vena cava. BACKGROUND TAVR is attractive in high-risk or inoperable patients with severe aortic stenosis. Available transcatheter valves require large introducer sheaths, which are a risk for major vascular complications or preclude TAVR altogether. Caval-aortic access has been successful in animals. METHODS We performed a single-center retrospective review of procedural and 30-day outcomes of prohibitive-risk patients who underwent TAVR via caval-aortic access. RESULTS Between July 2013 and January 2014, 19 patients underwent TAVR via caval-aortic access; 79% were women. Caval-aortic access and tract closure were successful in all 19 patients; TAVR was successful in 17 patients. Six patients experienced modified VARC-2 major vascular complications, 2 (11%) of whom required intervention. Most (79%) required blood transfusion. There were no deaths attributable to caval-aortic access. Throughout the 111 (range 39 to 229) days of follow up, there were no post-discharge complications related to tract creation or closure. All patients had persistent aorto-caval flow immediately post-procedure. Of the 16 patients who underwent repeat imaging after the first week, 15 (94%) had complete closure of the residual aorto-caval tract. CONCLUSIONS Percutaneous transcaval venous access to the aorta allows TAVR in otherwise ineligible patients, and may offer a new access strategy for other applications requiring large transcatheter implants.

The association of sex with outcomes among patients undergoing primary percutaneous coronary intervention for ST elevation myocardial infarction in the contemporary era: Insights from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2)

BACKGROUND historically, women with ST elevation myocardial infarction (STEMI) have had a higher mortality compared with men. It is unclear if these differences persist among patients undergoing contemporary primary percutaneous coronary intervention (PCI) with focus on early reperfusion. METHODS we assessed the impact of sex on the outcome of 8,771 patients with acute STEMI who underwent primary PCI from 2003 to 2008 at 32 hospitals participating in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium PCI registry. A propensity-matched analysis was performed to adjust for differences in baseline characteristics and comorbidities between men and women. RESULTS twenty-nine percent of the cohort was female. Compared with men, women were older and had more comorbidity. Female sex was associated with a higher unadjusted in-hospital mortality (6.02% vs 3.45%, odds ratio [OR] 1.79, 95% CI 1.45-2.22, P < .0001) and higher risk of contrast-induced nephropathy (OR 1.75, P < .0001), vascular complications (OR 2.13, P < .0001), and postprocedure transfusion (OR 2.84, P < .0001). The gap in sex-specific mortality narrowed over time. In a propensity-matched analysis, female sex was associated with a higher rate of transfusion (OR 1.88, 95% CI 1.57-2.24, P < .0001) and vascular complications (OR 1.65, 95% CI 1.26-2.14, P < .0002); but there was no difference in mortality (OR 1.30, 95% CI 0.98-1.72, P = .07). CONCLUSIONS women make up approximately one third of patients undergoing primary PCI for STEMI. Female sex is associated with an apparent hazard of increased mortality among patients undergoing primary PCI for STEMI, but this difference is likely explained by older age and worse baseline comorbidities among women.

First Clinical Application of an Actively Reversible Direct Factor IXa Inhibitor as an Anticoagulation Strategy in Patients Undergoing Percutaneous Coronary Intervention

Background— The ideal anticoagulant should prevent ischemic complications without increasing the risk of bleeding. Controlled anticoagulation is possible with the REG1 system, an RNA aptamer pair comprising the direct factor IXa inhibitor RB006 and its active control agent RB007. Methods and Results— This phase 2a study included a roll-in group (n=2) treated with REG1 plus glycoprotein IIb/IIIa inhibitors followed by 2 groups randomized 5:1 to REG1 or unfractionated heparin. In group 1 (n=12), RB006 was partially reversed with RB007 after percutaneous coronary intervention and fully reversed 4 hours later. In group 2 (n=12), RB006 was fully reversed with RB007 immediately after percutaneous coronary intervention. Femoral sheaths were removed after complete reversal. Patients were pretreated with aspirin and clopidogrel. End points included major bleeding within 48 hours; composite of death, myocardial infarction, or urgent target vessel revascularization within 14 days; and pharmacodynamic measures. All cases were successful, with final Thrombolysis in Myocardial Infarction grade 3 flow and no angiographic thrombotic complications. There were 2 ischemic end points in the REG1 group and 1 in the unfractionated heparin group, with 1 major bleed in the unfractionated heparin group. Median activated clotting time values rose from 151 to 236 seconds after RB006. Administration of the partial RB007 dose reversed anticoagulation to an intermediate activated clotting time value of 186 seconds. Complete reversal with RB007 returned the median activated clotting time value to 144 seconds. Both reversal strategies enabled scheduled femoral sheath removal. Conclusions— This study demonstrates the clinical translation of a novel platform of anticoagulation targeting factor IXa and its active reversal to percutaneous coronary intervention and provides the basis for further investigation. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00715455.

Transcutaneous ultrasound-facilitated coronary thrombolysis during acute myocardial infarction

In preclinical experiments, the combination of transcutaneous, low-frequency ultrasound and thrombolytic therapy has shown improved patency rates over thrombolytics alone. A total of 25 patients with myocardial infarction were treated with a thrombolytic agent and adjunctive transcutaneous ultrasound. No unanticipated major adverse events were observed.

Thirty-Day Readmissions after Transcatheter Aortic Valve Replacement in the United States: Insights from the Nationwide Readmissions Database

Background— Readmissions after cardiac procedures are common and contribute to increased healthcare utilization and costs. Data on 30-day readmissions after transcatheter aortic valve replacement (TAVR) are limited. Methods and Results— Patients undergoing TAVR (International Classification of Diseases-Ninth Revision-CM codes 35.05 and 35.06) between January and November 2013 who survived the index hospitalization were identified in the Nationwide Readmissions Database. Incidence, predictors, causes, and costs of 30-day readmissions were analyzed. Of 12 221 TAVR patients, 2188 (17.9%) were readmitted within 30 days. Length of stay >5 days during index hospitalization (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.24–1.73), acute kidney injury (HR, 1.23; 95% CI, 1.05–1.44), >4 Elixhauser comorbidities (HR, 1.22; 95% CI, 1.03–1.46), transapical TAVR (HR, 1.21; 95% CI, 1.05–1.39), chronic kidney disease (HR, 1.20; 95% CI, 1.04–1.39), chronic lung disease (HR, 1.16; 95% CI, 1.01–1.34), and discharge to skilled nursing facility (HR, 1.16; 95% CI, 1.01–1.34) were independent predictors of 30-day readmission. Readmissions were because of noncardiac causes in 61.8% of cases and because of cardiac causes in 38.2% of cases. Respiratory (14.7%), infections (12.8%), bleeding (7.6%), and peripheral vascular disease (4.3%) were the most common noncardiac causes, whereas heart failure (22.5%) and arrhythmias (6.6%) were the most common cardiac causes of readmission. Median length of stay and cost of readmissions were 4 days (interquartile range, 2–7 days) and

Transcatheter caval valve implantation using multimodality imaging: Roles of TEE, CT, and 3D printing

8302 (interquartile range,

First in human percutaneous implantation of a balloon expandable transcatheter heart valve in a severely stenosed native mitral valve.

5229–16 021), respectively. Conclusions— Thirty-day readmissions after TAVR are frequent and are related to baseline comorbidities, TAVR access site, and post-procedure complications. Awareness of these predictors can help identify and target high-risk patients for interventions to reduce readmissions and costs.