Randomized Trial of Targeted Transendocardial Mesenchymal Precursor Cell Therapy in Patients With Heart Failure.

BACKGROUND: Mesenchymal precursor cells (MPCs) are allogeneic, immunoselected cells with anti-inflammatory properties that could improve outcomes in heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: This study assessed the efficacy and safety of MPCs in patients with high-risk HFrEF. METHODS: This randomized, double-blind, multicenter study evaluated a single transendocardial administration procedure of MPCs or sham-control in 565 intention-to-treat patients with HFrEF on guideline-directed therapies. The primary endpoint was time-to-recurrent events caused by decompensated HFrEF or successfully resuscitated symptomatic ventricular arrhythmias. Hierarchical secondary endpoints included components of the primary endpoint, time-to-first terminal cardiac events, and all-cause death. Separate and composite major adverse cardiovascular events analyses were performed for myocardial infarction or stroke or cardiovascular death. Baseline and 12-month echocardiography was performed. Baseline plasma high-sensitivity C-reactive protein levels were evaluated for disease severity. RESULTS: The primary endpoint was similar between treatment groups (HR: 1.17; 95% CI: 0.81-1.69; P = 0.41) as were terminal cardiac events and secondary endpoints. Compared with control subjects, MPCs increased left ventricular ejection fraction from baseline to 12 months, especially in patients with inflammation. MPCs decreased the risk of myocardial infarction or stroke by 58% (HR: 0.42; 95% CI: 0.23-0.76) and the risk of 3-point major adverse cardiovascular events by 28% (HR: 0.72; 95% CI: 0.51-1.03) in the analysis population (n = 537), and by 75% (HR: 0.25; 95% CI: 0.09-0.66) and 38% (HR: 0.62; 95% CI: 0.39-1.00), respectively, in patients with inflammation (baseline high-sensitivity C-reactive protein ≥2 mg/L). CONCLUSIONS: The primary and secondary endpoints of the trial were negative. Positive signals in prespecified, and post hoc exploratory analyses suggest MPCs may improve outcomes, especially in patients with inflammation.

The REDUCE HTN: REINFORCE: Randomized, Sham-Controlled Trial of Bipolar Radiofrequency Renal Denervation for the Treatment of Hypertension.

OBJECTIVES: The aim of this study was to investigate bipolar radiofrequency renal denervation in patients with hypertension not receiving medications at baseline. BACKGROUND: A blood pressure-reducing effect of renal denervation has been difficult to isolate in clinical investigations. METHODS: REDUCE HTN: REINFORCE (Renal Denervation Using the Vessix Renal Denervation System for the Treatment of Hypertension) was a randomized, sham-controlled multicenter trial. Patients with office systolic blood pressure (SBP) of 150 to 180 mm Hg and average 24-h ambulatory SBP of 135 to 170 mm Hg after medication washout underwent bipolar radiofrequency renal denervation or a sham procedure. The planned outcome was 8-week change in 24-h ambulatory SBP. Enrollment was terminated for apparent futility before a sufficient sample for powered efficacy comparisons was enrolled. Safety assessments included all-cause death, renal failure, severe hypotension or syncope, hypertensive crisis, and renal artery stenosis. RESULTS: Baseline 24-h blood pressure was 148.3 ± 10.9/85.7 ± 9.1 mm Hg for the denervation group (n = 34, mean age 58.5 ± 10.1 years, 47% women) and 149.1 ± 7.2/86.4 ± 9.8 mm Hg for the control group (n = 17, mean age 58.2 ± 9.8 years, 24% women). At 8 weeks, mean 24-h SBP reductions for the renal denervation and control groups were -5.3 mm Hg (95% confidence interval [CI]: -8.8 to -1.8 mm Hg) and -8.5 mm Hg (95% CI: -13.3 to -3.8 mm Hg), respectively (difference 3.3 mm Hg; 95% CI: -2.8 to 9.3 mm Hg; p = 0.30). Antihypertensive medications could then be added. By 6 months, decreases in SBP were greater for the denervation group, yielding between-group differences of -7.2 mm Hg (95% CI: -15.2 to 0.8 mm Hg; p = 0.08), -9.7 mm Hg (95% CI: -17.7 to -1.7 mm Hg; p = 0.02), and -11.4 mm Hg (95% CI: -19.2 to -3.7 mm Hg; p < 0.01) for 24-h, daytime ambulatory, and office measurements, respectively. Through 12 months, 1 patient (renal denervation group) had a hypertensive urgency requiring immediate management, and 1 experienced progression of renal artery stenosis. CONCLUSIONS: Future studies of radiofrequency renal denervation must anticipate delayed treatment effects. (Renal Denervation Using the Vessix Renal Denervation System for the Treatment of Hypertension [REDUCE HTN: REINFORCE]; NCT02392351).

Long-Term Safety and Efficacy of Platinum Chromium Everolimus-Eluting Stents in Coronary Artery Disease: 5-Year Results From the PLATINUM Trial.

OBJECTIVES: The authors sought to evaluate the final 5-year safety and effectiveness of the platinum-chromium everolimus-eluting stent (PtCr-EES) in the randomized trial, as well as in 2 single-arm substudies that evaluated PtCr-EES in small vessels (diameter <2.5 mm; n = 94) and long lesions (24 to 34 mm; n = 102). BACKGROUND: In the multicenter, randomized PLATINUM (PLATINUM Clinical Trial to Assess the PROMUS Element Stent System for Treatment of De Novo Coronary Artery Lesions), the PtCr-EES was noninferior to the cobalt-chromium everolimus-eluting stent (CoCr-EES) at 1 year in 1,530 patients undergoing percutaneous coronary intervention. METHODS: Patients with 1 or 2 de novo coronary artery lesions (reference vessel diameter 2.50 to 4.25 mm, length ≤24 mm) were randomized 1:1 to PtCr-EES versus CoCr-EES. All patients in the substudies received PtCr-EES. The primary endpoint was target lesion failure (TLF), a composite of target vessel-related cardiac death, target vessel-related myocardial infarction, or ischemia-driven target lesion revascularization. RESULTS: In the randomized trial, the 5-year TLF rate was 9.1% for PtCr-EES and 9.3% for CoCr-EES (hazard ratio [HR]: 0.97; p = 0.87). Landmark analysis demonstrated similar TLF rates from discharge to 1 year (HR: 1.12; p = 0.70) and from 1 to 5 years (HR: 0.90; p = 0.63). There were no significant differences in the rates of cardiac death, myocardial infarction, target lesion or vessel revascularization, or stent thrombosis. PtCr-EES had 5-year TLF rates of 7.0% in small vessels and 13.6% in long lesions. CONCLUSIONS: PtCr-EES demonstrated comparable safety and effectiveness to CoCr-EES through 5 years of follow-up, with low rates of stent thrombosis and other adverse events. The 5-year event rates were also acceptable in patients with small vessels and long lesions treated with PtCr-EES. (The PLATINUM Clinical Trial to Assess the PROMUS Element Stent System for Treatment of De Novo Coronary Artery Lesions [PLATINUM]; NCT00823212; The PLATINUM Clinical Trial to Assess the PROMUS Element Stent System for Treatment of De Novo Coronary Artery Lesions in Small Vessels [PLATINUM SV]; NCT01498692; The PLATINUM Clinical Trial to Assess the PROMUS Element Stent System for Treatment of Long De Novo Coronary Artery Lesions [PLATINUM LL]; NCT01500434).

Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial.

BACKGROUND: Sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA2a) activity is deficient in the failing heart. Correction of this abnormality by gene transfer might improve cardiac function. We aimed to investigate the clinical benefits and safety of gene therapy through infusion of adeno-associated virus 1 (AAV1)/SERCA2a in patients with heart failure and reduced ejection fraction. METHODS: We did this randomised, multinational, double-blind, placebo-controlled, phase 2b trial at 67 clinical centres and hospitals in the USA, Europe, and Israel. High-risk ambulatory patients with New York Heart Association class II-IV symptoms of heart failure and a left ventricular ejection fraction of 0·35 or less due to an ischaemic or non-ischaemic cause were randomly assigned (1:1), via an interactive voice and web-response system, to receive a single intracoronary infusion of 1 × 10(13) DNase-resistant particles of AAV1/SERCA2a or placebo. Randomisation was stratified by country and by 6 min walk test distance. All patients, physicians, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was time to recurrent events, defined as hospital admission because of heart failure or ambulatory treatment for worsening heart failure. Primary efficacy endpoint analyses and safety analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01643330. FINDINGS: Between July 9, 2012, and Feb 5, 2014, we randomly assigned 250 patients to receive either AAV1/SERCA2a (n=123) or placebo (n=127); 243 (97%) patients comprised the modified intention-to-treat population. Patients were followed up for at least 12 months; median follow-up was 17·5 months (range 1·8-29·4 months). AAV1/SERCA2a did not improve time to recurrent events compared with placebo (104 vs 128 events; hazard ratio 0·93, 95% CI 0·53-1·65; p=0·81). No safety signals were noted. 20 (16%) patients died in the placebo group and 25 (21%) patients died in the AAV1/SERCA2a group; 18 and 22 deaths, respectively, were adjudicated as being due to cardiovascular causes. INTERPRETATION: CUPID 2 is the largest gene transfer study done in patients with heart failure so far. Despite promising results from previous studies, AAV1/SERCA2a at the dose tested did not improve the clinical course of patients with heart failure and reduced ejection fraction. Although we did not find evidence of improved outcomes at the dose of AAV1/SERCA2a studied, our findings should stimulate further research into the use of gene therapy to treat patients with heart failure and help inform the design of future gene therapy trials. FUNDING: Celladon Corporation.

Three-year results comparing platinum-chromium PROMUS element and cobalt-chromium XIENCE V everolimus-eluting stents in de novo coronary artery narrowing (from the PLATINUM Trial).

In the randomized PLATINUM trial, the PROMUS Element platinum-chromium everolimus-eluting stent (PtCr-EES; Boston Scientific, Natick, Massachusetts) was noninferior to the XIENCE V cobalt-chromium everolimus-eluting stent (CoCr-EES; Boston Scientific and Abbott Vascular, Santa Clara, California) for the primary end point of 1-year target lesion failure. This study reports the 3-year outcomes. Patients (n=1,530) with 1 or 2 de novo native coronary artery lesions (baseline vessel diameter≥2.50 mm to ≤4.25 mm and length≤24 mm) were randomized 1:1 to PtCr-EES versus CoCr-EES. Three-year follow-up was available in 93.9% (703 of 749) of patients with CoCr-EES and 96.7% (733 of 758) of patients with PtCr-EES. Comparing CoCr-EES with PtCr-EES, 3-year rates of death (4.3% vs 3.7%, hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.52 to 1.48, p=0.62), cardiac death (1.9% vs 1.2%, HR 0.63, 95% CI 0.27 to 1.45, p=0.27), myocardial infarction (2.5% vs 2.3%, HR 0.92, 95% CI 0.48 to 1.79, p=0.81), ischemia-driven target lesion revascularization (4.9% vs 3.5%, HR 0.72, 95% CI 0.43 to 1.20, p=0.21), and Academic Research Consortium definite or probable stent thrombosis (0.5% vs 0.7%, HR 1.23, 95% CI 0.33 to 4.57, p=0.76) were not significantly different. In conclusion, 3-year results of the PLATINUM randomized, controlled, clinical trial demonstrate comparable safety and efficacy outcomes of the PROMUS Element PtCr-EES and the XIENCE V CoCr-EES.

Recombinant nematode anticoagulant protein c2 in patients with non-ST-segment elevation acute coronary syndrome: the ANTHEM-TIMI-32 trial.

OBJECTIVES: We sought to evaluate the safety and efficacy of recombinant nematode anticoagulant protein c2 (rNAPc2) in patients with non-ST-segment elevation acute coronary syndrome (nSTE-ACS). BACKGROUND: Recombinant NAPc2 is a potent inhibitor of the tissue factor/factor VIIa complex that has the potential to reduce ischemic complications mediated by thrombin generation. METHODS: A total of 203 patients were randomized 4:1 to double-blinded intravenous rNAPc2 or placebo every 48 h for a total of 1 to 3 doses in 8 ascending panels (1.5 to 10 microg/kg). All patients received aspirin, unfractionated heparin (UFH), or enoxaparin and early catheterization; clopidogrel and glycoprotein IIb/IIIa blockers were encouraged. Two subsequent open-label panels evaluated 10 mug/kg rNAPc2 with half-dose UFH (n = 26) and no UFH (n = 26). The primary end point was the rate of major plus minor bleeding. Pharmacokinetics, pharmacodynamics, continuous electrocardiography, and clinical events were assessed. RESULTS: Recombinant NAPc2 did not significantly increase major plus minor bleeding (3.7% vs. 2.5%; p = NS) despite increasing the international normalized ratio in a dose-related fashion (trend p < or = 0.0001). Higher-dose rNAPc2 (> or =7.5 microg/kg) suppressed prothrombin fragment F1.2 generation compared with placebo and reduced ischemia by >50% compared to placebo and lower-dose rNAPc2. Thrombotic bailout requiring open-label anticoagulant occurred in 5 of 26 patients treated without UFH, but none in the half-dose UFH group (19% vs. 0%; p = 0.051). CONCLUSIONS: In patients with nSTE-ACS managed with standard antithrombotics and an early invasive approach, additional proximal inhibition of the coagulation cascade with rNAPc2 was well tolerated. rNAPc2 doses > or =7.5 microg/kg suppressed F1.2 and reduced ischemia, though some heparin may be necessary to avoid procedure-related thrombus formation. (Anticoagulation With rNAPc2 to Eliminate MACE/TIMI 32; http://www.clinicaltrial.gov/ct/show/NCT00116012?order=1; NCT00116012).

Optical characterization of Pseudomonas fluorescens on meat surfaces using time-resolved fluorescence.

A scanning optical system for the detection of bacteria on meat surfaces based on fluorescence lifetime and intensity measurements is described. The system detects autofluorescent light emitted by naturally occurring fluorophores in bacteria. The technique only requires minimal sample preparation and handling, thus the chemical properties of the specimen are preserved. This work presents the preliminary results obtained from a time-resolved fluorescence imaging system for the characterization of a nonpathogenic gram-negative bacteria, Pseudomonas fluorescens. Initial results indicate that the combination of fluorescence lifetime and intensity measurements provides a means for characterizing biological media and for detecting microorganisms on surfaces.