Kenneth W. Baran

Effect of Intracoronary Delivery of Autologous Bone Marrow Mononuclear Cells 2 to 3 Weeks Following Acute Myocardial Infarction on Left Ventricular Function The LateTIME Randomized Trial

CONTEXT Clinical trial results suggest that intracoronary delivery of autologous bone marrow mononuclear cells (BMCs) may improve left ventricular (LV) function when administered within the first week following myocardial infarction (MI). However, because a substantial number of patients may not present for early cell delivery, the efficacy of autologous BMC delivery 2 to 3 weeks post-MI warrants investigation. OBJECTIVE To determine if intracoronary delivery of autologous BMCs improves global and regional LV function when delivered 2 to 3 weeks following first MI. DESIGN, SETTING, AND PATIENTS A randomized, double-blind, placebo-controlled trial (LateTIME) of the National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network of 87 patients with significant LV dysfunction (LV ejection fraction [LVEF] ≤45%) following successful primary percutaneous coronary intervention (PCI) between July 8, 2008, and February 28, 2011. INTERVENTIONS Intracoronary infusion of 150 × 10(6) autologous BMCs (total nucleated cells) or placebo (BMC:placebo, 2:1) was performed within 12 hours of bone marrow aspiration after local automated cell processing. MAIN OUTCOME MEASURES Changes in global (LVEF) and regional (wall motion) LV function in the infarct and border zone between baseline and 6 months, measured by cardiac magnetic resonance imaging. Secondary end points included changes in LV volumes and infarct size. RESULTS A total of 87 patients were randomized (mean [SD] age, 57 [11] years; 83% men). Harvesting, processing, and intracoronary delivery of BMCs in this setting was feasible. Change between baseline and 6 months in the BMC group vs placebo for mean LVEF (48.7% to 49.2% vs 45.3% to 48.8%; between-group mean difference, -3.00; 95% CI, -7.05 to 0.95), wall motion in the infarct zone (6.2 to 6.5 mm vs 4.9 to 5.9 mm; between-group mean difference, -0.70; 95% CI, -2.78 to 1.34), and wall motion in the border zone (16.0 to 16.6 mm vs 16.1 to 19.3 mm; between-group mean difference, -2.60; 95% CI, -6.03 to 0.77) were not statistically significant. No significant change in LV volumes and infarct volumes was observed; both groups decreased by a similar amount at 6 months vs baseline. CONCLUSION Among patients with MI and LV dysfunction following reperfusion with PCI, intracoronary infusion of autologous BMCs vs intracoronary placebo infusion, 2 to 3 weeks after PCI, did not improve global or regional function at 6 months. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00684060.

Integration of pre-hospital electrocardiograms and ST-elevation myocardial infarction receiving center (SRC) networks: impact on Door-to-Balloon times across 10 independent regions.

OBJECTIVES The aim of this study was to evaluate the rate of timely reperfusion for ST-elevation myocardial infarction (STEMI) with primary percutaneous coronary intervention (PPCI) in regional STEMI Receiving Center (SRC) networks. BACKGROUND The American College of Cardiology Door-to-Balloon (D2B) Alliance target is a >75% rate of D2B <or=90 min. Independent initiatives nationwide have organized regional SRC networks that coordinate universal access to 9-1-1 with the pre-hospital electrocardiogram (PH-ECG) diagnosis of STEMI and immediate transport to a SRC (designated PPCI-capable hospital). METHODS A pooled analysis of 10 independent, prospective, observational registries involving 72 hospitals was performed. Data were collected on all consecutive patients with a PH-ECG diagnosis of STEMI. The D2B and emergency medical services (EMS)-to-balloon (E2B) times were recorded. RESULTS Paramedics transported 2,712 patients with a PH-ECG diagnosis of STEMI directly to the nearest SRC. A PPCI was performed in 2,053 patients (76%) with an 86% rate of D2B <or=90 min (95% confidence interval: 84.4% to 87.4%). Secondary analyses of this cohort demonstrated a 50% rate of D2B <or=60 min (n = 1,031), 25% rate of D2B <or=45 min (n = 517), and an 8% rate of D2B <or=30 min (n = 155). A tertiary analysis restricted to 762 of 2,053 (37%) cases demonstrated a 68% rate of E2B <or=90 min. CONCLUSIONS Ten independent regional SRC networks demonstrated a combined 86% rate of D2B <or=90 min, and each region individually surpassed the American College of Cardiology D2B Alliance benchmark. In areas with regional SRC networks, 9-1-1 provides entire communities with timely access to quality STEMI care.

Combination reperfusion therapy with eptifibatide and reduced-dose tenecteplase for ST-elevation myocardial infarction: results of the integrilin and tenecteplase in acute myocardial infarction (INTEGRITI) Phase II Angiographic Trial

OBJECTIVES The goal of this study was to evaluate combinations of eptifibatide with reduced-dose tenecteplase (TNK) in ST-elevation myocardial infarction (STEMI). BACKGROUND Glycoprotein IIb/IIIa inhibitors enhance thrombolysis. The role of combination therapy in clinical practice remains to be established. METHODS Patients (n = 438) with STEMI <6 h were enrolled. In dose-finding, 189 patients were randomized to different combinations of double-bolus eptifibatide and reduced-dose TNK. In dose-confirmation, 249 patients were randomized 1:1 to eptifibatide 180 microg/kg bolus, 2 microg/kg/min infusion, and 180 microg/kg bolus 10 min later (180/2/180) plus half-dose TNK (0.27 mg/kg) or standard-dose (0.53 mg/kg) TNK monotherapy. All patients received aspirin and unfractionated heparin (60 U/kg bolus; infusion 7 U/kg/h [combination], 12 U/kg/h [monotherapy]). The primary end point was Thrombolysis In Myocardial Infarction (TIMI) grade 3 epicardial flow at 60 min. RESULTS In dose-finding, TIMI grade 3 flow rates were similar across groups (64% to 68%). Arterial patency was highest for eptifibatide 180/2/180 plus half-dose TNK (96%, p = 0.02 vs. eptifibatide 180/2/90 plus half-dose TNK). In dose-confirmation, this combination, compared with TNK monotherapy, tended to achieve more TIMI 3 flow (59% vs. 49%, p = 0.15), arterial patency (85% vs. 77%, p = 0.17), and ST-segment resolution (median 71% vs. 61%, p = 0.08) but was associated with more major hemorrhage (7.6% vs. 2.5%, p = 0.14) and transfusions (13.4% vs. 4.2%, p = 0.02). Intracranial hemorrhage occurred in 1.0%, 0.6%, and 1.7% of patients treated with any combination, eptifibatide 180/2/180 and half-dose TNK, and TNK monotherapy, respectively. CONCLUSIONS Double-bolus eptifibatide (180/2/180) plus half-dose TNK tended to improve angiographic flow and ST-segment resolution compared with TNK monotherapy but was associated with more transfusions and non-cerebral bleeding. Further study is needed before this combination can be recommended for general use.

Early Access to the Cardiac Catheterization Laboratory for Patients Resuscitated From Cardiac Arrest Due to a Shockable Rhythm: The Minnesota Resuscitation Consortium Twin Cities Unified Protocol

Background In 2013 the Minnesota Resuscitation Consortium developed an organized approach for the management of patients resuscitated from shockable rhythms to gain early access to the cardiac catheterization laboratory (CCL) in the metro area of Minneapolis‐St. Paul. Methods and Results Eleven hospitals with 24/7 percutaneous coronary intervention capabilities agreed to provide early (within 6 hours of arrival at the Emergency Department) access to the CCL with the intention to perform coronary revascularization for outpatients who were successfully resuscitated from ventricular fibrillation/ventricular tachycardia arrest. Other inclusion criteria were age >18 and <76 and presumed cardiac etiology. Patients with other rhythms, known do not resuscitate/do not intubate, noncardiac etiology, significant bleeding, and terminal disease were excluded. The primary outcome was survival to hospital discharge with favorable neurological outcome. Patients (315 out of 331) who were resuscitated from VT/VF and transferred alive to the Emergency Department had complete medical records. Of those, 231 (73.3%) were taken to the CCL per the Minnesota Resuscitation Consortium protocol while 84 (26.6%) were not taken to the CCL (protocol deviations). Overall, 197 (63%) patients survived to hospital discharge with good neurological outcome (cerebral performance category of 1 or 2). Of the patients who followed the Minnesota Resuscitation Consortium protocol, 121 (52%) underwent percutaneous coronary intervention, and 15 (7%) underwent coronary artery bypass graft. In this group, 151 (65%) survived with good neurological outcome, whereas in the group that did not follow the Minnesota Resuscitation Consortium protocol, 46 (55%) survived with good neurological outcome (adjusted odds ratio: 1.99; [1.07–3.72], P=0.03). Conclusions Early access to the CCL after cardiac arrest due to a shockable rhythm in a selected group of patients is feasible in a large metropolitan area in the United States and is associated with a 65% survival rate to hospital discharge with a good neurological outcome.

Effect of stenosis on exercise-induced dilation of large coronary arteries*

The effects of a flow-limiting stenosis on external circumflex coronary arterial diameter during treadmill exercise were studied in 10 instrumented dogs. Coronary arterial diameter was measured by sonomicrometry proximal to the stenosis-producing hydraulic occluder so that the effects of a post-stenotic pressure drop were excluded. With no stenosis, heart rate increased (116 +/- 7 to 183 +/- 10 beats/min, p less than 0.001), aortic pressure increased (97 +/- 3 to 105 +/- 5 mm Hg. p less than 0.005), circumflex coronary blood flow increased (48 +/- 8 to 72 +/- 8 ml/min, p less than 0.001), and circumflex coronary diameter increased (3.82 +/- 0.29 to 3.93 +/- 0.27 mm, p less than 0.01). In the presence of a flow-limiting stenosis, heart rate increased (120 +/- 6 to 176 +/- 9 beats/min, p less than 0.001), aortic pressure did not change significantly (95 +/- 4 to 92 +/- 4 mm Hg), circumflex coronary blood flow increased slightly (39 +/- 8 to 46 +/- 9 ml/min, p less than 0.005), and circumflex coronary arterial diameter did not change significantly (3.78 +/- 0.29 to 3.80 +/- 0.28 mm). The stenosis prevented the increase in aortic pressure, blunted the increase in circumflex coronary blood flow (24 +/- 4 versus 7 +/- 2 ml/min, p less than 0.005), and prevented the increase in circumflex coronary arterial diameter. Therefore normal coronary arteries dilated during exercise and a flow-limiting stenosis prevented exercise-induced coronary dilation proximal to the stenosis, possibly due to both the failure of aortic pressure to increase and less flow-induced endothelium-dependent dilation.

Very Rapid Treatment of ST-Segment―Elevation Myocardial Infarction: Utilizing Prehospital Electrocardiograms to Bypass the Emergency Department

Prehospital ECG (PH-ECG) has been identified as a strategy to help reduce door-to-balloon (D2B) time during emergency treatment with percutaneous coronary intervention (PCI) for patients with ST-elevation myocardial infarction (STEMI).1 National Registry of Myocardial Infarction data from 2000–2002 suggest utilization rates of PH-ECG of 7000 patients with acute coronary syndrome transported by emergency medical services (EMS) during 2007 found PH-ECG utilization rates of 27.4%.3 Among this cohort, D2B times were significantly shorter than the cohort of patients without PH-ECG, and there was a trend toward lower in-hospital mortality. Systems of care that have incorporated PH-ECGs into a citywide or region-wide strategy have demonstrated a significant reduction in D2B times, usually by triaging patients in the prehospital setting, bypassing non-PCI-capable hospitals, and transporting patients directly to a designated STEMI receiving center (SRC) capable of providing primary PCI.4,5 Rapid and accurate interpretation of the PH-ECG is a critical step in the process of incorporating PH-ECG into systems of care for acute STEMI. Different models for interpretation of PH-ECGs have been described, including computer algorithm interpretation, wireless transmission to designated centers for physician interpretation, and direct paramedic interpretation.1 Previous studies demonstrated that trained EMS personnel can reliably identify STEMI on the PH-ECG.6,7 We initiated a program to evaluate a novel strategy to reduce D2B time for patients with STEMI who undergo PCI. The intent was to expedite prehospital triage and to reduce emergency department (ED) delays to treatment with PCI for patients with acute STEMI. We empowered EMS personnel to interpret the PH-ECG in the prehospital setting and then to activate the cardiac catheterization laboratory (CV laboratory) staff before transporting the patient to …

Real-Time Decision Support to Guide Percutaneous Coronary Intervention Bleeding Avoidance Strategies Effectively Changes Practice Patterns

Approximately 600 000 percutaneous coronary interventions (PCIs) are performed annually in the United States.1 Periprocedural bleeding is a common complication of PCI,2–6 occurring in 2% to 6% of cases.6–12 Bleeding is associated with major adverse events, including short- and long-term mortality,4,8–11,13 as well as prolonged hospital length of stay (LOS)7–10,14 and higher hospital costs.6,7,15,16 Periprocedural bleeding seems to be predictable and modifiable.4 A validated risk prediction algorithm may help clinicians estimate bleeding risk in patients undergoing PCI, and established bleeding avoidance strategies (BAS), such as bivalirudin, radial artery access, and vascular closure devices, have been demonstrated to reduce bleeding.2,16–24 However, recent studies have reported that patients at highest risk for bleeding are least likely to receive treatment with BAS.2,5 Accurate preprocedure bleeding risk assessment scoring may provide a significant opportunity for physicians to selectively use effective preventative tactics in patients most likely to benefit and improve PCI safety, care quality, and subsequently hospitalization costs. Bleeding events after cardiovascular procedures have been identified by the Centers for Medicare and Medicaid Services to be quality indicators among centers participating in its Acute Care Episode demonstration.2 However, data on the impact of pre-PCI bleeding risk assessment on physician practice patterns, BAS use, and quality outcomes are sparse. We developed a quality improvement program for PCI patients using a preprocedure bleeding risk score to stimulate the use of consensus BAS in high-risk, high-cost patients. The specific aims of the program were to improve patient safety and care quality and to decrease LOS and hospital costs by reducing bleeding events and associated complications in PCI patients. An interdisciplinary team …

The TIME Trial - Effect of Timing of Stem Cell Delivery Following ST-Elevation Myocardial Infarction on the Recovery of Global and Regional Left Ventricular Function: Final 2-Year Analysis

Rationale: The TIME trial (Timing in Myocardial Infarction Evaluation) was the first cell therapy trial sufficiently powered to determine if timing of cell delivery after ST-segment–elevation myocardial infarction affects recovery of left ventricular (LV) function. Objective: To report the 2-year clinical and cardiac magnetic resonance imaging results and their modification by microvascular obstruction. Methods and Results: TIME was a randomized, double-blind, placebo-controlled trial comparing 150 million bone marrow mononuclear cells versus placebo in 120 patients with anterior ST-segment–elevation myocardial infarctions resulting in LV dysfunction. Primary end points included changes in global (LV ejection fraction) and regional (infarct and border zone) function. Secondary end points included changes in LV volumes, infarct size, and major adverse cardiac events. Here, we analyzed the continued trajectory of these measures out to 2 years and the influence of microvascular obstruction present at baseline on these long-term outcomes. At 2 years (n=85), LV ejection fraction was similar in the bone marrow mononuclear cells (48.7%) and placebo groups (51.6%) with no difference in regional LV function. Infarct size and LV mass decreased ≥30% in each group at 6 months and declined gradually to 2 years. LV volumes increased ≈10% at 6 months and remained stable to 2 years. Microvascular obstruction was present in 48 patients at baseline and was associated with significantly larger infarct size (56.5 versus 36.2 g), greater adverse LV remodeling, and marked reduction in LV ejection fraction recovery (0.2% versus 6.2%). Conclusions: In one of the longest serial cardiac magnetic resonance imaging analyses of patients with large anterior ST-segment–elevation myocardial infarctions, bone marrow mononuclear cells administration did not improve recovery of LV function over 2 years. Microvascular obstruction was associated with reduced recovery of LV function, greater adverse LV remodeling, and more device implantations. The use of cardiac magnetic resonance imaging leads to greater dropout of patients over time because of device implantation in patients with more severe LV dysfunction resulting in overestimation of clinical stability of the cohort. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00684021.

Effect of Pinacidil on Myocardial Blood Flow in the Presence of a Coronary Artery Stenosis

This study examined the effect of pinacidil on transmural distribution of myocardial blood flow during normal conditions and in the presence of a coronary artery stenosis. Studies were performed in 11 awake dogs; blood flow was measured with radioactive microspheres. Two doses of pinacidil were administered to decrease mean arterial pressure (MAP) by –10 mm Hg (low dose, 0.18 ± 0.02 mg/kg) and 20 mm Hg (high dose, 0.32 ± 0.03 mg/kg). Measurements were performed during unimpeded arterial inflow and with two levels of coronary stenosis that limited blood flow to −60% above (moderate stenosis) and –30% above basal flow (severe stenosis). With no stenosis, coronary flow increased 227 ± 17% after low-dose and 321 ± 31% after high-dose pinacidil (each p < 0.01). During control conditions, subendocardial (endo) flow exceeded subepicardial (epi) flow (endo/ epi ratio = 1.33). This ratio was not changed by low-dose pinacidil but decreased to 0.93 after high-dose pinacidil (p < 0.05). During high-dose pinacidil, a coronary stenosis caused uniform reduction of blood flow across the left ventricular wall, with no further significant change in the ratio of endo/epi flow. With low-dose pinacidil, both moderate and severe degrees of stenosis caused redistribution of flow away from the subendocardium similar to that observed with high-dose pinacidil. Although a stenosis that limited the increase in mean coronary flow after pinacidil administration to 162% of the predrug control value had a 95% probability of not causing a decrease in absolute subendocardial flow, the data suggest that pinacidil could have potential for aggravating subendocardial ischemia in severe occlusive coronary artery disease.

Cell therapy and satellite centers: The cardiovascular cell therapy research network experience

Due to the changing population in patients with myocardial infarction, recruiting patients in clinical trials continues to challenge clinical investigators. The Cardiovascular Cell Therapy Research Network (CCTRN) chose to expand the reach and power of its recruitment effort by incorporating both referral and treatment satellite centers. Eight treatment satellites were successfully identified and they screened patients over a two year period. The result of this effort was an increase in recruitment, with these treatment satellites contributing 30% of the patients to two of the three Network studies. The hurdles that these satellite treatment centers faced and how they surmounted them provide instruction to clinical research groups eager to expand to satellite systems and to health care practitioners who are interested in taking part in multicenter clinical trials.