Aspirin for the Prevention of Recurrent Venous Thromboembolism After a First Unprovoked Event: Results of the ASPIRE Randomized Controlled Trial.

A Randomized Trial of Bedside Platelet-Function Monitoring to Adjust Antiplatelet Therapy versus Standard of Care in Patients Undergoing Drug-Eluting Stent Implantation: The ARCTIC Study.

First Large-scale Platelet-Function Evaluation in an Acute Coronary Syndromes Trial: The TRILOGY ACS Platelet-function Substudy.

Results of the Trial to Assess Chelation Therapy.

Main Results of the Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) Trial.

Background. Patients’ responses to oral antiplatelet therapy are subject to variation. Bedside monitoring offers the opportunity to improve outcomes after coronar y stenting by individualizing therapy.

Methods. We randomly assigned 2440 patients scheduled for coronary stenting at 38 centers to a strategy of platelet-function monitoring, with drug adjustment in patients who had a poor response to antiplatelet therapy, or to a conventional strategy without monitoring and drug adjustment. The primary end point was the composite of death, MI, stent thrombosis, stroke, or urgent revascularization 1 year after stent implantation. For patients in the monitoring group, the VerifyNow P2Y12 and aspirin point-of-care assays were used in the catheterization laboratory before stent implantation and in the outpatient clinic 2 to 4 weeks later.

Results. In the monitoring group, high platelet reactivity in patients taking clopidogrel (34.5% of patients) or aspirin (7.6%) led to the administration of an additional bolus of clopidogrel, prasugrel, or aspirin along with glycoprotein IIb/IIIa inhibitors during the procedure. The primary end point occurred in 34.6% of the patients in the monitoring group, as compared with 31.1% of those in the conventional-treatment group (HR=1.13; 95% CI, 0.98 to 1.29; P=.10). The main secondary end point, stent thrombosis or any urgent revascularization, occurred in 4.9% of the patients in the monitoring group and 4.6% of those in the conventional-treatment group (HR=1.06; 95% CI, 0.74 to 1.52; P=.77). The rate of major bleeding events did not differ significantly between groups.

Conclusions. This study showed no significant improvements in clinical outcomes with platelet-function monitoring and treatment adjustment for coronary stenting, as compared with standard antiplatelet therapy without monitoring.

Background. The relationship of platelet function testing measurements with outcomes in patients with acute coronary syndromes (ACS) initially managed medically without revascularization is unknown. The objective of the study was to characterize the differences and evaluate clinical outcomes associated with platelet reactivity among patients with ACS treated with clopidogrel or prasugrel.

Methods. Patients with medically managed unstable angina or non–ST-segment elevation MI were enrolled in the TRILOGY ACS trial (20 08 to 2011) comparing clopidogrel versus prasugrel. Of 9326 participants, 27.5% were included in a platelet function substudy: 1286 treated with prasugrel and 1278 treated with clopidogrel. Aspirin with either prasugrel (10 or 5mg/d) or clopidogrel (75mg/d) was given. Patients aged 75 or older, or those younger than 75 but who weighed less than 60kg, received a maintenance dose of prasugrel (5mg). The main outcome was platelet reactivity, measured in P2Y12 reaction units (PRUs) at baseline, at 2hours, and at 1, 3, 6, 12, 18, 24, and 30 months after randomization. The primary efficacy end point was a composite of cardiovascular death, MI, or stroke through 30 months.

Results. Among participants younger than 75 years and weighing 60kg or more, the median PRU values at 30 days were 64 (interquartile range [IQR], 33-128) in the prasugrel group versus 200 (IQR, 141-260) in the clopidogrel group (P<.001), a difference that persisted through all subsequent time points. For participants younger than 75 years and weighing less than 60kg, the median 30-day PRU values were 139 (IQR, 86-203) for the prasugrel group versus 209 (IQR, 148-283) for the clopidogrel group (P<.001), and for participants 75 years or older, the median PRU values were 164 (IQR, 105-216) for the prasugrel group versus 222 (IQR, 148-268) for the clopidogrel group (P<.001). At 30 months the rate of the primary efficacy end point was 17.2% (160 events) in the prasugrel group versus 18.9% (180 events) in the clopidogrel group (P=.29). There were no significant differences in the continuous distributions of 30-day PRU values for participants with a primary efficacy end point event after 30 days (n=214) compared with participants without an event (n=1794; P=.07) and no significant relationship between the occurence of the primary efficacy end point and continuous PRU values (adjusted HR [HR] for increase of 60 PRUs, 1.03; 95% CI, 0.96-1.11; P=.44). Similar findings were observed with 30-day PRU cut points used to define high on-treatment platelet reactivity—PRU more than 208 (adjusted HR, 1.16; 95% CI, 0.89-1.52, P=.28) and PRU more than 230 (adjusted HR, 1.20; 95% CI, 0.90-1.61; P=.21).

Conclusions. Among patients with ACS, without ST-segment ele vation, and initially manage d without re vascularization, prasugrel was associate d with lower platelet reactivity than clopidogrel, irrespective of age, weight, and dose. Among those in the platelet substudy, no significant differences existed between prasugrel versus clopidogrel in the occurrence of the primary efficacy end point through 30 months and no significant association existed between platelet reactivity and occurrence of ischemic outcomes.

Background. According to reports from the CDC, the use of chelation therapy with disodium ethylene diamine tetra acetic acid (EDTA) therapy to treat atherosclerosis is increasing in the United States. Whether or not it is safe or effective cannot be determined based on current clinical data. The purpose of the study was to evaluate the safety and effectiveness of an EDTA chelation solution versus placebo in post-MI patients.

Methods. This randomized study included 1708 post-MI patients (≥6 weeks post-MI) who also received standard care, aged ≥50 years with an average follow-up of 4 years. The intervention consisted of 40 infusions of an EDTA-chelation solution and of an oral, high-dose, multivitamin and mineral supplement versus placebo. The primary composite end point was mortality (all-cause), MI, stroke, coronary revascularization, or angina hospitalization. Secondary end points were composite CV death, nonfatal MI, nonfatal stroke

Results. Composite endpoints: 18% re duction EDTA versus placebo (P=.035); Analysis by subgroups: Diabetes: 39% reduction in composite endpoints versus placebo (P=.002); Nondiabetics: 0.04% reduction versus placebo (P=.725); Anterior MI: 37% reduction versus placebo.

Conclusions. Post-MI patients who received chelation therapy had fewer clinical events compared to placebo. Two groups benefited most: diabetics and those who had experienced an anterior MI. Additional research is needed to confirm these findings and to understand the mechanisms of action for the benefits seen in this trial.

Bac kgr ound. In some r andomize d trials com paring revascularization strategies for patients with diabetes, coronary-artery bypass graf ting (CABG) has had a b etter outcome than percutaneous coronary intervention (PCI). We sought to discover whether aggressive medical therapy and the use of drug-eluting stents could alter the revascularization approach for patients with diabetes and multivessel coronary artery disease (CAD).

Methods. In this randomized trial, we assigned patients with diabetes and multivessel CAD to undergo either PCI with drug- eluting stents or CABG. The patients were followed for a minimum of 2 years (median among survivors, 3.8 years). All patients were prescrib e d currently recommende d me dical therapies for the control of low-density lipoprotein cholesterol, systolic blood pressure (BP), and glycated hemoglobin. The primary outcome measure was a composite of death from any cause, nonfatal MI, or nonfatal stroke.

Results. From 2005 through 2010, we enrolled 1900 patients at 140 international centers. The patients’ mean age was 63.1±9.1 years, 29% were women, and 83% had 3-vessel disease. The primary outcome occurred more frequently in the PCI group (P=.005), with 5-year rates of 26.6% in the PCI group and 18.7% in the CABG group. The benefit of CABG was driven by differences in rates of both MI (P<.001) and death from any cause (P=.049). Stroke was more frequent in the CABG group, with 5-year rates of 2.4% in the PCI group and 5.2% in the CABG group (P=.03).

Conclusions. For patients with diabetes and advanced CAD, CABG was superior to PCI in that it significantly reduced rates of death and MI, with a higher rate of stroke.

Background. The aim was to compare costs of PCI between centers without and with on-site cardiac surgery.

Methods. The study groups consisted of 14 149 (no on-site surgery centers) and 4718 patients (on-site surgery centers). Cost data were collected from inpatient bills and estimated the costs for outpatient cardiac procedures, inpatient stays, emergency-department visits, physician visits, and ambulance transportation costs.

Results. Patients undergoing PCI at centers with cardiac surgery on-site had slightly lower average costs over 9 months than similar patients treated at centers without surgery, but the difference in cost was statistically nonsignificant. The costs of the procedures at the centers without surgery were statistically sensitive to variations in annual PCI volume, with higher-volume centers generally incurring lower per-procedure costs. Most important, the study requirement that PCI patients at the nonsurgery centers be treated in the intensive-care unit after their procedure had a “dramatic” effect on the costs, even though patients treated at the nonsurgery cent ers had a short er length of hospitalization on average. Periprocedural costs were greater in the low-volume centers than at high-volume centers, especially among the centers with no on-site cardiac surgery. These differences were related not to differences in implant costs but to the total costs in the cath lab. No patients at centers with on-site surgery were required to receive postprocedural care in an ICU or CCU.

Conclusions. Although PCI costs slightly less in centers with cardiac-surgery capabilities than in centers without them, the difference appears to be related to center volume rather than the direct benefits of on-site emergency surgical backup.

Background. This study examined quality of life outcomes in the Trial to Assess Chelation Therapy (TACT).

Methods. This is a NIH-funde d, randomize d, double-blind, placebo-controlled, 2 × 2 factorial trial comparing 40 infusions of an ethylene diamine tetra-acetic (EDTA)-chelation solution with placebo in patients with CAD. In a random sample of the 50% of patients in TACT (n=911 of a total 1708 patients), quality of life was assessed at baseline and at 6, 12, and 24 months. The quality-of-life tests included the Medical Outcomes Study Short Form-36 (SF-36), including its Mental Health Inventory-5 (MHI-5) component that assessed anxiety and depression. The MHI-5 along with the Duke Activity Status Index (DASI), a measure of cardiac functional status, were “co-principal end points” for the analysis. Also included were the Seattle Angina Questionnaire (SAQ) Anginal Frequency and Quality of Life subscales.

Results. Chelation therapy had almost no effect on standard measurements of quality of life, compared to placebo. The exception was slight improvement in self-reported anginal symptoms with chelation therapy at 1 year (P=.016). However, according to the SAQ, about 80% of the patients had no anginal symptoms at baseline, so it was a small minority of the total population.

Conclusions. Obtained improvements in quality of life were very small and not associated with chelation. The quality-of-life results do not support clinical results.

Background. Although earlier studies have suggested that PCI could be more cost-effective than CABG, there has not been a study that compares the cost-effectiveness of PCI with drug-eluting stents (DES-PCI) t o C ABG in diab e tic patients having multi v essel revascularization. The purpose of the study was to evaluate cost- effectiveness of CABG versus DES-PCI for diabetic patients having multivessel revascularization. These results will compliment the clinical results of the FREEDOM trial.

Methods. Diabetic patients (n=1900) with multivessel CAD were randomized to either DES-PCI or CABG. Follow-up: 5 years. The primary endpoint was incremental cost-effectiveness ratio (ICER), or cost per quality-adjusted life year gained (QALY).

Results. Initial costs: CABG cost $8622/patient more than DES-PCI (P<.001). Five-year costs: CABG cost $3641/patient and yielded 0.031

QALY improvement and a ICER gain of $116 699/QALY. Lifetime cost- effectiveness ratio: 0.66 gain in QALY, CABG costs of $5392/patient (ICER gain of $8132/QALY for CABG).

Conclusions. For diabetic patients with multivessel disease, initial costs were higher for CABG than for PCI because of hospital stay and early complications. Total 5-year costs for CABG were also higher, but the follow-up costs for PCI were greater. However, based on lifetime projections, CABG was found to be more cost-effective compared to DES-PCI.

Background. Postoperative AF or flutter is one of the most common complications of cardiac surgery and significantly increases morbidity and health care utilization. A few small trials have evaluated whether long-chain n-3-PUFA reduce postoperative AF, with mixed results. The aim was to determine whether perioperative n-3-PUFA supplementation reduces postoperative AF.

Methods. The Omega-3 Fatty Acids for Prevention of Post- operative Atrial Fibrillation (OPERA) double-blind, placebo-controlled, randomized clinical trial. A total of 1516 patients scheduled for cardiac surgery in 28 centers in the United States, Italy, and Argentina were enrolled between August 2010 and June 2012. Inclusion criteria were broad; the main exclusions were regular use of fish oil or absence of sinus rhythm at enrollment. Patients were randomized to receive fish oil (1-g capsules containing ≥840mg n-3-PUFA as ethyl esters) or placebo, with preoperative loading of 10g over 3 to 5 days (or 8g over 2 days) followed postoperatively by 2g/d until hospital discharge or postoperative day 10, whichever came first. The main outcome measure was the occurrence of postoperative AF lasting longer than 30seconds. Secondary end points were postoperative AF lasting longer than 1 hour, resulting in sym ptoms, or treate d with cardioversion; postoperative AF excluding atrial flutter; time to first postoperative AF; number of AF episodes per patient; hospital utilization; and major adverse CV events, 30-day mortality, bleeding, and other adverse events.

Results. At enrollment, mean age was 64 (SD, 13) years; 72.2% of patients were men and 51.8% had planned valvular surgery. The primary end point occurred in 233 (30.7%) patients assigned to placebo and 227 (30.0%) assigned to n-3-PUFAs (odds ratio, [OR]=0.96; 95% CI, 0.77-1.20; P=.74). None of the secondary end points were significantly different between the placebo and fish oil groups, including postoperative AF that was sustained, symptomatic, or treated (231 [30.5%] vs 224 [29.6%]; P=.70) or number of postoperative AF episodes per patient (1 episode, 156 [20.6%] vs 157 [20.7%]; 2 episodes, 59 [7.8%] vs 49 [6.5%]; ≥3 episodes, 18 [2.4%] vs 21 [2.8%]); (P=.73). Supplementation with n-3-PUFA was generally well tolerated, with no evidence for increased risk of bleeding or serious adverse events.

Conclusion. In this large multinational trial among patients undergoing cardiac surgery, perioperative supplementation with n-3-PUFA, compare d with placebo, did not re duce the risk of postoperative AF.

Background. Although multivitamins are used to prevent vitamin and mineral deficiency, there is a perception that multivitamins may prevent cardiovascular disease (CVD). Observational studies have shown inconsistent associations between regular multivitamin use and CVD, with no long-term clinical trials of multivitamin use. The objective was to determine whether long-term multivitamin supplementation decreases the risk of major cardiovascular events among men.

Methods. The Physicians’ Health Study II, a randomized, double- blind, placebo-controlled trial of a common daily multivitamin, began in 1997 with continued treatment and follow-up through June 1, 2011. A total of 14 641 male US physicians initially aged 50 years or older (mean, 64.3 [SD, 9.2] years), including 754 men with a history of CVD at randomization, were enrolled. Patients were randomized to daily multivitamin or placebo. The main outcome measures were the composite end point of major cardiovascular events, including nonfatal MI, nonfatal stroke, and CVD mortality. Secondary outcomes included MI and stroke individually.

Results. During a median follow-up of 11.2 [interquartile range, 10.7-13.3] years, there were 1732 confirmed major cardiovascular events. Compared with placebo, there was no significant effect of a daily multivitamin on major cardiovascular events (11 and 10.8 events per 1000 person-years for multivitamin vs placebo, respectively; HR=1.01; 95%CI, 0.91-1.10; P=.91). Further, a daily multivitamin had no effect on total MI (3.9 and 4.2 events per 1000 person-years; HR=0.93; 95% CI, 0.80-1.09; P=.39), total stroke (4.1 and 3.9 events per 1000 person-years; HR= 1.06; 95% CI, 0.91-1.23; P=.48), or CVD mortality (5.0 and 5.1 events per 1000 person-years; HR=0.95; 95% CI, 0.83-1.09; P=.47). A daily multivitamin was also not significantly associated with total mortality (HR=0.94; 95% CI, 0.88-1.02; P=.13). The effect of a daily multivitamin on major cardiovascular events did not differ between men with or without a baseline history of CVD (P=.62 for interaction).

Conclusions. Among this population of US male physicians, taking a daily multivitamin did not reduce major cardiovascular events, MI, stroke, and CVD mortality after more than a decade of treatment and follow-up.

Background. Preventive therapies that address multiple CV risk factors are limited. Novel approaches are needed. A CVD preventive strategy consisting of a combination of aspirin, a statin, and 2 BP-lowering agents is one option that may reduce CV events. The objective of the study was to test the polypill compared to usual medications in patients with established CVD and those who are at high risk to increase adherence to guideline-indicated therapy and improve BP and LDL-cholesterol (LDL-C) in people at high risk.

Methods. This study randomized 2004 subjects from India and Europe to a polypill strategy, fixed-dose combination (FDC) or usual care (UC). Two versions were applied: a) aspirin 75mg, simvastatin 40mg, lisinopril 10mg and atenolol 50mg, or b) hydrochlorothiazide 12.5mg instead of atenolol. The primary outcome was adherence to indicated medications, based on self-report.

Results. Adherence was 86% on FDC, 65% on UC with 1.22 treatment effect (95% CI, 1.24-1.41).

Conclusions. Improvement in adherence occurs with FDC, including antiplatelet, statin and BP-lowering drugs. Both BP and cholesterol also improved in patients with CVD and a 33% increase in adherence in 15 months was reported.

Background. An estimated 10% to 20% of patients cannot tolerate statins or adequate doses to achieve treatment goals. Plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low- density lipoprotein (LDL) receptors, promoting their degradation and increasing LDL cholesterol levels. In phase 1 studies, a human monoclonal antibody to PCSK9, AMG145, was well tolerated and reduced LDL cholesterol levels. The objective of the study was to assess the efficacy and tolerability of AMG145 in patients with statin intolerance due to muscle-related side effects.

Methods. This is a 12-week, randomized, double-blind, placebo- and ezetimibe-controlled, dose-ranging study conducted between July 2011 and May 2012 in statin-intolerant adult patients at 33 international sites. Patients were randomized equally to 1 of 5 groups: AMG145 alone at doses of 280mg, 350mg, or 420mg; AMG145 at 420mg plus 10mg of ezetimibe; or 10mg of ezetimibe plus placebo. AMG145 or placebo was administered subcutaneously every 4 weeks. The primary end point was percentage change from baseline to week 12 in ultracentrifugation-measured LDL cholesterol. Other end points included measures of safety and tolerability of different doses of AMG145 and AMG145 plus ezetimibe.

Results. Of 236 patients screened, 160 were randomized (mean age, 62 years; 64% female; mean baseline LDL cholesterol, 193mg/dL); all patients had intolerance to 1 or more statins because of muscle- related events. At week 12, mean changes in LDL cholesterol levels were −67mg/dL (−41%; 95% CI, −49% to −33%) for the AMG145, 280-mg, group; −70mg/dL (−43%; 95% CI, −51% to −35%) for the 350-mg group; −91mg/dL (−51%; 95% CI, −59% to −43%) for the 420-mg group; and −110mg/dL (−63%; 95% CI, −71% to −55%) for the 420-mg/ezetimibe group compared with −14mg/dL (−15%; 95% CI, −23% to −7.0%) for the placebo/ezetimibe group (P<.001). Four serious adverse events were reported with AMG145 (CAD, acute pancreatitis, hip fracture, syncope). Myalgia was the most common treatment- emergent adverse event during the study, occurring in 5 patients (15.6%) in the 280-mg group (n=32); 1 patient (3.2%) in the 350-mg group (n=31), 1 patient (3.1%) in the 420-mg group (n=32), 6 patients (20%) receiving 420-mg AMG145/ezetimibe, and 1 patient (3.1%) receiving placebo/ezetimibe.

Conclusions. In this phase 2 study in statin-intolerant patients, subcutaneous administration of a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels and was associated with short-term tolerability.

Background. Proprotein convertase subtilisin kexin type 9 (PCSK9) binds to LDL-C receptors preventing LDL-C clearance, therefore increasing LDL-C levels in the blood. RN316, a humanized monoclonal antibody, binds to PCK9 preventing down-regulation of the LDL-C receptors, which has been shown to improve LDL-C clearance, and therefore reducing LDL-C levels. The objective of the study was to evaluate effects of RN316 on LDL-C levels in patients on high-to- maximal doses of atorvastatin, rosuvastatin, or simvastatin.

Methods. In this Phase 2, double-blind, randomized, placebo- controlled study, 135 patients already undergoing statin treatment were randomized to 1 of 5 treatment arms: placebo, 0.25mg/kg, 1.0mg/kg, 3.0mg/kg, or 6.0mg/kg of RN316 administered every 4 weeks for 12 weeks with an 8-week follow-up period.

Results. LDL-C levels were significantly decreased with 3mg/kg and 6mg/kg dose of RN316 in addition to high- or maximal-dosage statin treatment. Total cholesterol was also reduced and levels of HDL-C increased. No significant changes were observed in triglycerides across any of the 5 treatment arms. Very few drug-related adverse events were observed. Those that did occur were mild and resolved with no intervention. The effect on LDL-C persisted for 4 weeks posttreatment.

Conclusions. RN316 significantly lowered LDL-C in addition to high or maximal statin dosage and was generally safe and well tolerated.

Background. In observational analyses, higher levels of high- density lipoprotein (HDL) cholesterol have been associated with a lower risk of coronary heart disease events. However, whether raising HDL cholesterol levels therapeutically reduces CV risk remains uncertain. Inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels and might therefore improve CV outcomes.

Methods. We randomly assigned 15 871 patients who had a recent ACS to receive the CETP inhibitor dalcetrapib at a dose of 600mg daily or placebo, in addition to the best available evidence-based care. The primary efficacy end point was a composite of death from coronary heart disease, nonfatal MI, ischemic stroke, unstable angina, or cardiac arrest with resuscitation.

Results. At the time of randomization, the mean HDL cholesterol level was 42mg per deciliter (1.1 mmol per liter), and the mean low- density lipoprotein (LDL) cholesterol level was 76mg per deciliter (2 mmol per liter). Over the course of the trial, HDL cholesterol levels increased from baseline by 4% to 11% in the placebo group and by 31% to 40% in the dalcetrapib group. Dalcetrapib had a minimal effect on LDL cholesterol levels. Patients were followed for a median of 31 months. At a prespecified interim analysis that included 1135 primary end-point events (71% of the projected total number), the independent data and safety monitoring board recommended termination of the trial for futility. As compared with placebo, dalcetrapib did not alter the risk of the primary end point (cumulative event rate, 8.0% and 8.3%, respectively; HR with dalcetrapib, 1.04; 95% confidence interval, 0.93 to 1.16; P=.52) and did not have a significant effect on any component of the primary end point or total mortality. The median C-reactive protein level was 0.2mg/L higher and the mean systolic BP was 0.6mm Hg higher with dalcetrapib, compared with placebo (P<.001 for both comparisons).

Conclusions. In patients with a recent ACS, dalcetrapib increased HDL cholesterol levels but did not reduce the risk of recurrent CV events.

Background. While the delivery of cell therapy after ST-segment elevation myocardial infarction (STEMI) has been evaluated in previous clinical trials, the influence of the timing of cell delivery on the effect on left ventricular function has not been analyzed. The objective of the study was to determine the effect of intracoronary autologous bone marrow mononuclear cell (BMC) delivery after STEMI on recovery of global and regional left ventricular function and whether timing of BMC delivery (3 days vs 7 days after reperfusion) influences this effect.

Methods. A randomized, 2 × 2 factorial, double-blinded, placebo- controlled trial, Timing In Myocardial infarction Evaluation (TIME) enrolled 120 patients with left ventricular dysfunction (left ventricular ejection fraction [LVEF] ≤45%) after successful primary PCI of anterior STEMI between July 17, 2008, and November 15, 2011, as part of the Cardiovascular Cell Therapy Research Network sponsored by the National Heart, Lung, and Blood Institute. The intervention consisted of intracoronary infusion of 150 × 106 BMCs or placebo (randomized 2:1) within 12hours of aspiration and cell processing administered at day 3 or day 7 (randomized 1:1) after treatment with PCI. The primary end points were change in global (LVEF) and regional (wall motion) left ventricular function in infarct and border zones at 6 months measured by cardiac magnetic resonance imaging and change in left ventricular function as affected by timing of treatment on day 3 versus day 7. The secondary end points included major adverse CV events as well as changes in left ventricular volumes and infarct size.

Results. The mean (SD) patient age was 56.9 (10.9) years and 87.5% of participants we re male. At 6 months, there was no significant increase in LVEF for the BMC group (45.2% [95% CI, 42.8% to 47.6%] to 48.3% [95% CI, 45.3% to 51.3%) versus the placebo group (44.5% [95% CI, 41.0% to 48.0%] to 47.8% [95% CI, 43.4% to 52.2%]) (P=.96). There was no significant treatment effect on regional left ventricular function observed in either infarct or border zones. There were no signif icant dif ferences in change in global left ventricular function for patients treated at day 3 (−0.9% [95% CI,−6.6% to 4.9%], P=.76) or day 7 (1.1% [95%CI, −4.7% to 6.9%], P=.70). The timing of treatment had no significant effect on regional left ventricular function recovery. Major adverse events were rare among all treatment groups.

Conclusions. Among patients with STEMI treated with primary PCI, the administration of intracoronary BMCs at either 3 days or 7 days after the event had no significant effect on recovery of global or regional left ventricular function compared with placebo.

Background. Mesenchymal stem cells (MSCs) are under evaluation as a therapy for ischemic cardiomyopathy (ICM). Both autologous and allogeneic MSC therapies are possible; however, their safety and efficacy have not been compared. The objective was to test whether allogeneic MSCs are as safe and effective as autologous MSCs in patients with left ventricular (LV) dysfunction due to ICM.

Methods. A phase 1/2 randomized comparison (POSEIDON study) in a US tertiary-care referral hospital of allogeneic and autologous MSCs in 30 patients with LV dysfunction due to ICM between April 2, 2010, and September 14, 2011, with 13-month follow-up. Twenty million, 100 million, or 200 million cells (5 patients in each cell type per dose level) were delivered by transendocardial stem cell injection into 10 LV sites. Main outcome measures were 30-day postcatheterization incidence of predefined treatment-emergent serious adverse events (SAEs). Efficacy assessments include d 6-minute walk test, exercise peak VO2, Minnesota Living with Heart Failure Questionnaire (MLHFQ), New York Heart Association class, LV volumes, ejection fraction (EF), early enhancement defect (EED; infarct size), and sphericity index.

Results. Within 30 days, 1 patient in each group (treatment- emergent SAE rate, 6.7%) was hospitalized for heart failure, less than the prespecified stopping event rate of 25%. The 1-year incidence of SAEs was 33.3% (n=5) in the allogeneic group and 53.3% (n=8) in the autologous group (P=.46). At 1 year, no ventricular arrhythmia SAEs were observed among allogeneic recipients compared with 4 patients (26.7%) in the autologous group (P=.10). Relative to baseline, autologous but not allogeneic MSC therapy was associated with an improvement in the 6-minute walk test and the MLHFQ score, but neither improved exercise VO2 max. Allogeneic and autologous MSCs reduced mean EED by −33.21% (95% CI, −43.61% to −22.81%; P<.001) and sphericity index but did not increase EF. Allogeneic MSCs reduced LV end-diastolic volumes. Low-dose concentration MSCs (20 million cells) produced greatest reductions in LV volumes and increased EF. Allogeneic MSCs did not stimulate signif icant donor-specific alloimmune reactions.

Conclusions. In this early-stage study of patients with ICM, transendocardial injection of allogeneic and autologous MSCs without a placebo control were both associated with low rates of treatment- emergent SAEs, including immunologic reactions. In aggregate, MSC injection favorably affected patient functional capacity, quality of life, and ventricular remodeling.

Background. The aim was to evaluate the usefulness of cardiac stem-cell (CSC), instead of cells derived from bone marrow, in heart- failure patients.

Methods. This is a phase 1, randomized, open-label trial of c-KIT- positive CSCs in patients with left ventricular dysfunction (LVEF <40%) following an MI. In the trial, the cells were harvested from the patient's right atrial appendage, isolated and expanded, and then infused to repair an infarction during coronary bypass surgery.

Results. Echocardiography showed the average LVEF in the 18 patients treated with the CSC infusion increased from 29.0% before infusion to 36.0% (P<.001) 4 months after the procedure. During that period, LVEF improved only from 29.2% to 29.4% in 13 control patients. The benefits seen in the treated group grew relative to the control group at 1-year and 2-year follow-up. The average LVEF grew insignificantly from 30.3% at baseline to 31.7% at 1 year post-procedure in the 12 control patients followed that long. In 17 patients in the CSC-treatment group at 1-year follow-up, LVEF increased to 37.8% from a baseline average of 29.7%. At 2 years, 5 control patients still showed no significant change in LVEF, while average LVEF rose to 41.7% in the 12 CSC-treated patients who had reached the 2-year follow-up. Global wall-motion scores declined slightly in the control group over 24 months but improved from –2.50 to –3.92 (P=.006) in the treatment group. Cardiac MRI showed that the CSC-treated patients had statistically significant improvements in mass of nonviable myocardial tissue and the percentages of viable tissue within the infarcted region. Minnesota Heart Failure Scores improved significantly in the CSC-treated patients while remaining almost flat in the control group. No adverse effects attributable to CSCs have been reported in the trial out to 2 years.

Conclusions. CSC is a useful treatment in patients with left ventricular dysfunction. Further studies are required to evaluate its potential.

Background. The objective of the study was to evaluate if biventricular (BiV) pacing can prevent progression of heart failure and its clinical and economic consequences in patients with AV block.

Methods. Eligibility criteria were a) AV block necessitating pacing; b) LVEF <50%; c) NYHA class I, II or III; d) absence of a class I indication for CRT; and e) no previous pacemaker or ICD. Echocardiography was performed at randomization, 6, 12, 18 and 24 months. The primary end point was the composite of all-cause mortality, heart failure- related urgent care or increase in LV end-systolic volume.

Results. A total of 691 patients were randomized; 349 were allocated to BiV pacing and 342 to RV pacing. Average follow-up was more than 36 months in both groups. The primary endpoint was reached more frequently in the RV pacing group (HR=0.74; 95%CI, 0.6-0.8).

Conclusions. In patients with AV block and LV systolic dysfunction, BiV pacing compared to RV pacing leads to a significant 26% reduction in the combined end point of mortality, heart failure related urgent care and increase in LV end systolic volume.

Background. It is recommended that comatose survivors of out- of-hospital cardiac arrest should be cooled to 32° to 34°C for 12 to 24hours. However, the optimal level of cooling is unknown. The aim of this pilot study was to obtain initial data on the effect of different levels of hypothermia. We hypothesized that deeper temperatures will be associated with better survival and neurological outcome.

Methods. Patients were eligible if they had a witnessed out-of- hospital cardiac arrest from March 20 08 to August 2011. Target temperature was randomly assigned to 32°C or 34°C. Enrollment was stratified on the basis of the initial rhythm as shockable or asystole. The target temperature was maintained during 24hours followed by 12 to 24hours of controlled rewarming. The primary outcome was survival free from severe dependence (Barthel Index score ≥60 points) at 6 months.

Results. Thirty-six patients were enrolled in the trial (26 shockable rhythm, 10 asystole), with 18 assigned to 34°C and 18 to 32°C. Eight of 18 patients in the 32°C group (44.4%) met the primary end point compared with 2 of 18 in the 34°C group (11.1%) (log-rank P=.12). All patients whose initial rhythm was asystole died before 6 months in both groups. Eight of 13 patients with initial shockable rhythm assigned to 32°C (61.5%) were alive free from severe dependence at 6 months compared with 2 of 13 (15.4%) assigned to 34°C (log-rank P=.029). The incidence of complications was similar in both groups except for the incidence of clinical seizures, which was lower (1 versus 11; P=.0002) in patients assigned to 32°C compared with 34°C. On the contrary, there was a trend toward a higher incidence of bradycardia (7 versus 2; P=.054) in patients assigned to 32°C. Although potassium levels decreased to a greater extent in patients assigned to 32°C, the incidence of hypokalemia was similar in both groups.

Conclusions. The findings of this pilot trial suggest that a lower cooling level may be associated with a better outcome in patients surviving out-of-hospital cardiac arrest secondary to a shockable rhythm. The benefits observed here merit further investigation in a larger trial in out-of-hospital cardiac arrest patients with different presenting rhythms.

Background. Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic effects. In a pilot study, serelaxin was safe and well tolerated with positive clinical outcome signals in patients with acute heart failure. The RELAX-AHF trial tested the hypothesis that serelaxin-treated patients would have greater dyspnoea relief compared with patients treated with standard care and placebo.

Methods. RELAX-AHF was an international, double-blind, placebo- controlled trial, enrolling patients admitted to hospital for acute heart failure who were randomly assigned (1:1) via a central randomisation scheme blocked by study centre to standard care plus 48-h intravenous infusions of placebo or serelaxin (30μg/kg per day) within 16h from presentation. All patients had dyspnoea, congestion on chest radiograph, increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic BP greater than 125mm Hg. Patients, personnel administering study drug, and those undertaking study-related assessments were masked to treatment assignment. The primary endpoints evaluating dyspnoea improvement were change from baseline in the visual analogue scale area under the curve (VAS AUC) to day 5 and the pr oportion of patients with moderat e or mar k e d dy spnoea improvement measured by Likert scale during the first 24h, both analysed by intention to treat.

Results. 1161 patients were randomly assigned to serelaxin (n=581) or placebo (n=580). Serelaxin improved the VAS AUC primary dyspnoea endpoint (448mm × h, 95% CI 120—775; P=.007) compared with placebo, but had no significant effect on the other primary endpoint (Likert scale; placebo, 150 patients [26%]; serelaxin, 156 [27%]; P=.70). No significant effects were recorded for the secondary endpoints of cardiovascular death or readmission to hospital for heart failure or renal failure (placebo, 75 events [60-day Kaplan-Meier estimate, 13.0%]; serelaxin, 76 events [13.2%]; Hazard ratio [HR]=1.02 [95% CI, 0.74-1.41], P=.89] or days alive out of the hospital up to day 60 (placebo, 47.7 [12.1] days; serelaxin, 48.3 [11.6]; P=0.37). Serelaxin treatment was associated with significant reductions of other prespecified additional endpoints, including fewer deaths at day 180 (placebo, 65 deaths; serelaxin, 42; HR=0.63; 95% CI, 0.42-0.93; P=.019).

Conclusions. Treatment of acute heart failure with serelaxin was associated with dyspnoea relief and improvement in other clinical outcomes, but had no effect on readmission to hospital. Serelaxin treatment was well tolerated and safe, supported by the reduced 180- day mortality.

Background. Ultrafiltration is an alternative strategy to diuretic therapy for the treatment of patients with acute decompensated heart failure. Little is known about the ef f icacy and safety of ultrafiltration in patients with acute decompensated heart failure complicated by persistent congestion and worsened renal function.

Methods. We randomly assigned a total of 188 patients with acute decompensated heart failure, worsened renal function, and persistent congestion to a strategy of stepped pharmacologic therapy (94 patients) or ultrafiltration (94 patients). The primary end point was the bivariate change from baseline in the serum creatinine level and body weight, as assessed 96hours after random assignment. Patients were followed for 60 days.

Results. Ultrafiltration was inferior to pharmacologic therapy with respect to the bivariate end point of the change in the serum creatinine level and body weight 96hours after enrollment (P=.003), owing primarily to an increase in the creatinine level in the ultrafiltration group. At 96hours, the mean change in the creatinine level was−0.04±0.53mg/dL (−3.5±46.9μmol/L) in the pharmacologic-therapy group, as compared with +0.23±0.70mg/dL (20.3±61.9μmol/L) in the ultrafiltration group (P=.003). There was no significant difference in weight loss 96hours after enrollment between patients in the pharmacologic-therapy group and those in the ultrafiltration group (a loss of 5.5±5.1kg [12.1±11.3 lb] and 5.7±3.9kg [12.6±8.5 lb], respective ly; P =.58). A higher percentage of patients in the ultrafiltration group than in the pharmacologic-therapy group had a serious adverse event (72% vs 57%, P=.03).

Conclusions. In a randomized trial involving patients hospitalized for acute decompensated heart failure, worsened renal function, and persistent congestion, the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultraf iltration for the preservation of renal function at 96hours, with a similar amount of weight loss with the 2 approaches. Ultrafiltration was associated with a higher rate of adverse events.