Sex-based differences in outcomes with bivalirudin or unfractionated heparin for transcatheter aortic valve replacement: Results from the BRAVO-3 randomized trial.

BACKGROUND: Women comprise almost 50% of patients undergoing transcatheter aortic valve replacement (TAVR) and previous studies have indicated higher rates of procedural complications and bleeding in women compared to men. It is unknown whether men and women demonstrate a differential response to bivalirudin versus unfractionated heparin (UFH) in TAVR. We sought to evaluate outcomes by sex and type of anticoagulant from the Bivalirudin Versus Heparin Anticoagulation in Transcatheter Aortic Valve Replacement (BRAVO-3) trial of transfemoral TAVR. METHODS: BRAVO-3 was a randomized multicenter trial comparing transfemoral TAVR with bivalirudin versus UFH (31 centers, n = 802). The primary endpoint was 48 h major bleeding defined as Bleeding Academic Research Consortium (BARC) type ≥3b. Major adverse cardiovascular events (MACE) were a composite of 30-day death, myocardial infarction, or stroke. Net adverse cardiovascular events (NACE) were a composite of BARC ≥3b bleeding or 30-day MACE. We examined the outcomes in men and women. RESULTS: The total cohort included 49% women (n = 391, 195 received bivalirudin and 196 UFH) and 51% men (n = 411, 209 received bivalirudin and 202 UFH). Women were older than men with fewer comorbidities including coronary artery disease, atrial fibrillation, diabetes but similar EuroSCORE I. Women received smaller sheath and device sizes compared with men without differences in the use of vascular closure devices. At 48-hr post-TAVR there was no difference in bleeding or vascular complications in women compared to men. The use of bivalirudin did not result in significantly lower bleeding at 48 hr or 30-days compared to UFH. CONCLUSIONS: There was no difference in early outcomes with bivalirudin versus UFH in men or women undergoing contemporary TAVR. © 2016 Wiley Periodicals, Inc.

Autologous Mesenchymal Stem Cells Show More Benefit on Systolic Function Compared to Bone Marrow Mononuclear Cells in a Porcine Model of Chronic Myocardial Infarction.

Cardiac cell therapy is a strategy to treat patients with chronic myocardial infarction (MI). No consensus exists regarding the optimal cell type. First, a comparison between autologous bone marrow-derived mononuclear cells (BMMNC) and mesenchymal stem cells (MSC) on therapeutic efficacy after MI was performed. Next, the effect of repetitive, NOGA-guided transendocardial injection was determined via a crossover design. Nineteen pigs were allocated in three groups: (1) placebo (at 4 and 8 weeks), (2) MSC (followed by placebo at 8 weeks), or (3) BMMNC (followed by MSC at 8 weeks) delivery including a priming strategy to enhance MSC effect. At 4 weeks, ejection fraction (EF) was significantly improved after MSC injection and not by BMMNC injection. After 8 weeks, no difference was observed in EF between cell-treated groups demonstrating the positive systolic effect of MSC. This study showed that MSC rather than BMMNC injection improves systolic function in chronic MI.

Circulatory support devices: fundamental aspects and clinical management of bleeding and thrombosis.

Circulatory support devices are increasingly being used to overcome cardiac or respiratory failure. Long-term devices are used either as a 'bridge to transplant' to support patients who are unable to wait any longer for a heart transplant, or, more recently, as 'destination therapy' for older patients suffering from end-stage heart failure and who have contraindications to heart transplantation. Short-term support devices for high-risk percutaneous coronary intervention, or as a 'bridge for decision' for patients suffering from refractory cardiogenic shock, have also been developed. The clinical benefit of such assist devices has been demonstrated in several important studies, but, unfortunately, thrombotic and bleeding complications are two major clinical issues in patients requiring these devices. Overcoming these issues is of major importance to allow the safe and broad use of these devices, and to consider them as true alternatives to heart transplantation. The present review focuses on thrombotic and bleeding complications, and describes how the risk of thrombosis and bleeding may vary according to the clinical indication, but also according to the type of device. We describe the current knowledge of the mechanisms underlying the occurrence of these complications, provide some guidance for choosing the most appropriate anticoagulation regimen to prevent their occurrence for each type of device and indication, and provide some recommendations for the management of patients when the complication occurs.

Long-term safety of intramuscular gene transfer of non-viral FGF1 for peripheral artery disease.

Peripheral artery disease is a progressive disease. Primary ischemic leg symptoms are muscle fatigue, discomfort or pain during ambulation, known as intermittent claudication. The most severe manifestation of peripheral artery disease is critical limb ischemia (CLI). The long-term safety of gene therapy in peripheral artery disease remains unclear. This four center peripheral artery disease registry was designed to evaluate the long-term safety of the intramuscular non-viral fibroblast growth factor-1 (NV1FGF), a plasmid-based angiogenic gene for local expression of fibroblast growth factor-1 versus placebo in patients with peripheral artery disease who had been included in five different phase I and II trials. Here we report a 3-year follow-up in patients suffering from CLI or intermittent claudication. There were 93 evaluable patients, 72 of them in Fontaine stage IV (47 NV1FGF versus 25 placebo) and 21 patients in Fontaine stage IIb peripheral artery disease (15 NV1FGF versus 6 placebo). Safety parameters included rates of non-fatal myocardial infarction (MI), stroke, death, cancer, retinopathy and renal dysfunction. At 3 years, in 93 patients included this registry, there was no increase in retinopathy or renal dysfunction associated with delivery of this angiogenic factor. There was also no difference in the number of strokes, MI or deaths, respectively, for NV1FGF versus placebo. In the CLI group, new cancer occurred in two patients in the NV1FGF group. Conclusions that can be drawn from this relatively small patient group are limited because of the number of patients followed and can only be restricted to safety. Yet, data presented may be valuable concerning rates in cancer, retinopathy, MI or strokes following angiogenesis gene therapy in the absence of any long-term data in angiogenesis gene therapy. It may take several years until data from larger patient populations will become available.

Insights on the role of diabetes and geographic variation in patients with critical limb ischaemia.

BACKGROUND: Patients with critical limb ischaemia (CLI) unsuitable for revascularisation have a high rate of amputation and mortality (30% and 25% at 1 year, respectively). Localised gene therapy using plasmid DNA encoding acidic fibroblast growth factor (NV1FGF, riferminogene pecaplasmid) has showed an increased amputation-free survival in a phase II trial. This article provides the rationale, design and baseline characteristics of CLI patients enrolled in the pivotal phase III trial (EFC6145/TAMARIS). METHODS: An international, double-blind, placebo-controlled, randomised study composed of 525 CLI patients recruited from 170 sites worldwide who were unsuitable for revascularisation and had non-healing skin lesions was carried out to evaluate the potential benefit of repeated intramuscular administration of NV1FGF. Randomisation was stratified by country and by diabetic status. RESULTS: The mean age of the study cohort was 70 ± 10 years, and included 70% males and 53% diabetic patients. Fifty-four percent of the patients had previous lower-extremity revascularisation and 22% had previous minor amputation of the index leg. In 94% of the patients, the index leg had distal occlusive disease affecting arteries below the knee. Statins were prescribed for 54% of the patients, and anti-platelet drugs for 80%. Variation in region of origin resulted in only minor demographic imbalance. Similarly, while diabetic status was associated with a frequent history of coronary artery disease, it had little impact on limb haemodynamics and vascular lesions. CONCLUSIONS: Clinical characteristics and vascular anatomy of CLI patients with ischaemic skin lesions who were unsuitable for revascularisation therapy show little variations by region of origin and diabetic status. The findings from this large CLI cohort will contribute to our understanding of this disease process. This study is registered with ClinicalTrials.gov, number NCT00566657.

One-year clinical follow-up of a registry evaluating a percutaneous revascularisation strategy combining a pre-specified simple selection process with the use of a new thin-strut bare cobalt-chromium stent.

Objectives. To evaluate clinical events in a specifically selected cohort of patients with obstructive coronary artery disease (CAD), using a new generation thin-strut bare cobalt-chromium coronary stent.Methods. Patients with single- or multi-vessel, stable or unstable CAD eligible for percutaneous implantation of at least one bare cobalt-chromium stent were evaluated in a single-centre registry. Prospective pre-specified criteria for bare cobalt-chromium stent implantation in our centre were: any acute ST-elevation myocardial infarction (MI), otherwise 1) de novo coronary lesion, and 2) lesion length <20 mm, and 3) reference vessel diameter >2.6 mm, and 4) no diabetes, unless reference vessel diameter >3.5 mm. Endpoints, retrospectively collected, were death, MI and clinically driven target-lesion revascularisation (TLR) and target-vessel revascularisation (TVR) after 12 months.Results. Between September 2005 and June 2007, 712 patients (48.7% one-vessel, 29.9% two-vessel, 20% three-vessel and 1.4% left main disease; 7.9% diabetics) were treated with 800 bare cobalt-chromium stents, for stable angina (40.9%), unstable angina (20.9%) or acute ST-elevation MI (38.2%). The procedural success rate was 99.3%. Peri-procedural MI rate was 2.2% in the semi-elective group. At 12 months there were 17 deaths (2.4%), of which nine non-cardiac, 20 (2.8%) MI, 19 (2.7%) TLR and 29 (4.1%) TVR. Early and late definite stent thrombosis occurred in four (0.6%) and three (0.4%) patients, respectively.Conclusion. A strategy aimed at minimising drug-eluting stent use and combining a pre-specified simple selection process with the use of a new thin-strut bare cobalt-chromium stent is safe and effective at one-year clinical follow-up. (Neth Heart J 2010;18:486-92.).

Drug-eluting stents: trading restenosis for thrombosis?

Within the last 6 years, it has been demonstrated that drug-eluting stents (DES) reduce significantly angiographic and clinical restenosis after percutaneous coronary interventions. These results are consistent across several clinical randomized controlled trials comparing these new devices with bare metallic stents (BMS), which themselves have already markedly improved the results obtained with balloon angioplasty in the early days of this method of myocardial revascularization. Nevertheless, some concerns have been raised regarding a delayed endothelialization of the coated prostheses leading to late stent thrombosis occurring mainly when antiplatelet therapy is discontinued in the follow-up. The most recent data show that, in comparison with BMS, there is a small excess of late (> 1 year) stent thrombosis but this is not associated with an increased risk of death or myocardial infarction or all cause mortality. These concerns do not outweigh the strong benefits of DES in preventing restenosis but require a number of measures concerning a longer dual antiplatelet treatment (than initially expected), to control patient treatment compliance and to provide a complete education of patients and physicians. Future devices dealing with the two issues (antiproliferative properties with rapid controlled endothelialization preventing thrombosis) would be the next major advance in this rapidly evolving field.

Functional mitral regurgitation and chronic heart failure.

Functional mitral regurgitation (MR) frequently develops during the progression of chronic heart failure and predicts poor outcome. Impaired left ventricular (LV) function, LV remodeling associated with papillary muscle apical displacement and annular enlargement result in decreased mitral closing forces and tenting of the mitral valve at closure. Reduced closing forces and tenting both promote MR. Active myocardial ischemia, myocardial asynchronism and excessive loading conditions worsen MR at rest and during exercise. The therapeutic target in functional MR is the left ventricle and not the valve.

Cardiac resynchronisation therapy reduces functional mitral regurgitation during dynamic exercise in patients with chronic heart failure: an acute echocardiographic study.

OBJECTIVES: To assess non-invasively the acute effects of cardiac resynchronisation therapy (CRT) on functional mitral regurgitation (MR) at rest and during dynamic exercise. METHODS: 21 patients with left ventricular (LV) systolic dysfunction and functional MR at rest, treated with CRT, were studied. Each patient performed a symptom-limited maximal exercise with continuous two dimensional Doppler echocardiography twice. The first exercise was performed with CRT; the second exercise was performed without CRT. Mitral regurgitant flow volume (RV), effective regurgitant orifice area (ERO) and LV dP/dt were measured at rest and at peak exercise. RESULTS: CRT mildly reduced resting mitral ERO (mean 8 (SEM 2) v 11 (2) mm(2) without CRT, p = 0.02) and RV (13 (3) v 18 (3) ml without CRT, p = 0.03). CRT attenuated the spontaneous increase in mitral ERO and RV during exercise (1 (1) v 9 (2) mm(2), p = 0.004 and 1 (1) v 8 (2) ml, p = 0.004, respectively). CRT also significantly increased exercise-induced changes in LV dP/dt (140 (46) v 479 (112) mm Hg/s, p < 0.001). CONCLUSION: Attenuation of functional MR, induced by an increase in LV contractility during dynamic exercise, may contribute to the beneficial clinical outcome of CRT in patients with chronic heart failure and LV asynchrony.

[The use of the RESCUE thromboaspiration system in acute coronary syndrome]. / Thromboaspiration dans les syndromes coronaires aigus par le système RESCUE.

Interventional procedures associated with acute coronary syndromes or performed on saphenous bypass grafts frequently lead to embolic complications, resulting in no-reflow phenomenon, side-branch occlusion, or peri-procedural infarction. The RESCUE thrombo-aspiration system was used in 19 percutaneous coronary interventions. After initial use of the aspiration device, 81% of procedures were followed by stent deployment. TIMI flow 2 or higher was present in 42% at the beginning of the procedure and in 95% at the end. In-hospital MACE rate was 4.76%. This relatively user-friendly technique appears rapid and efficacious in the case of visible intracoronary thrombus.

[Restenosis and vascular response after angioplasty: physiopathological data]. / Resténose et réponse de la paroi vasculaire après angioplastie: aspects physiopathologiques.

Our purpose is to review the different mechanisms involved in the vascular response following percutaneous coronary revascularization, and their role in thrombotic complications and in restenosis. Specificities related to the various techniques of percutaneous coronary revascularization (balloon angioplasty, coronary stents, brachytherapy, drug eluting stents) are discussed.

[Does diabetes affect therapy in coronary patients? Revascularisation]. / Le diabète influence-t-il les choix thérapeutiques chez le coronarien? La revascularisation.

Techniques of myocardial revascularisation are very commonly employed in diabetic patients. In unstable angina, the reported data suggests a very significant benefit of an invasive strategy for the diabetic patient. In stable angina, subgroups analysis of randomised clinical trials carried out over ten years ago showed a better outcome after surgery in cases of multivessel disease. What has been the impact of technical advances archived since then? Active stents and antiplatelet drugs have considerably improved the outcome of diabetics treated by angioplasty. Cardiac surgery has also made considerable progress with the systematic use of arterial grafts. New randomised clinical trials are underway to determine the modern options of myocardial revascularisation for diabetic patients.

[Cell therapy to treat heart failure]. / Thérapie cellulaire et insuffisance cardiaque.

INTRODUCTION: Systolic heart failure is mainly due to a decreased left ventricular systolic function after myocardial infarction. Despite significant improvements in medical management of heart failure, the prognostic remains poor, with a 5-years survival only of 30%. PURPOSE: Current treatments are only able to delay progression toward end-stage heart failure. Heart transplantation is accessible only for selected patients. Thus, in the context of post-myocardial infarction, cell therapy appears to be a new original technique, available for the majority of patients and potentially non-invasive. CONCLUSION: After promising results in experimental models, a phase I clinical trial has been conducted in France, showing the feasibility of intracardiac autologous skeletal myoblast implantation. Other studies in Europe and USA are currently testing a variety of cells and delivery systems. A phase II-trial will begin in France.

[Coronary thrombosis imaging in humans]. / Imagerie de la thrombose coronaire chez l'homme.

The identification of coronary thrombosis in humans has important prognostic and therapeutic implications. Its recognition calls for invasive techniques: angioscopy, coronarography, and endocoronary ultrasound. Angioscopy allows visualisation of the arterial surface and the detection of thrombus with great sensitivity. Its presence is exclusive to the acute coronary syndromes: 67% in unstable angina, and 75% in myocardial infarction, although it is only present in 27% of cases of stable angina. The relative complexity of its use has led to the abandonment of this technique. Coronarography allows an indirect approach to coronary thrombosis. Certain aspects are evocative such as: intraluminal filling defect, complete occlusion with upstream convexity, ulceration and eccentric type 2 Ambrose classification plaques. As a function of the clinical presentation, the coronarographic views allow a good specificity for the diagnosis of thrombus. The sensitivity is weak, however, compared to angioscopy. Endocoronary ultrasound does not allow identification of fresh thrombus which is not echogenic and does not allow differentiation between older thrombus and lipid plaque. In the future, magnetic resonance imaging could prove interesting in the detection of recent thrombus.

Patency of percutaneous transluminal coronary angioplasty sites at 6-month angiographic follow-up: A key determinant of survival in diabetics after coronary balloon angioplasty.

BACKGROUND: Several reports have demonstrated a high mortality rate in diabetic patients treated by standard coronary balloon angioplasty. No clear explanation has been provided for this finding. METHODS AND RESULTS: Consecutive diabetic patients successfully treated by standard coronary balloon angioplasty (n=604) were enrolled in a follow-up program including repeated angiography at 6 months and long-term clinical follow-up. Clinical follow-up was available in 603 patients (99.8%). Twelve patients died, 2 underwent bypass surgery before scheduled repeated angiography, and 76 declined angiography. Determinants of long-term mortality were analyzed in the 513 patients with angiography at 6 months and long-term clinical follow-up (mean follow-up, 6.5+/-2.4 years). On the basis of the results of repeated angiography, 3 groups of patients were defined: group 1, 162 patients without restenosis (32%); group 2, 257 patients with nonocclusive restenosis (50%); and group 3, 94 patients with coronary occlusion (18%). Overall actuarial 10-year mortality rate was 36%. Actuarial 10-year mortality was 24% in group 1, 35% in group 2, and 59% in group 3 (P:<0.0001). Multivariate analysis demonstrated that coronary occlusion was a strong and independent correlate of long-term total mortality (hazard ratio, 2.16; 95% CI, 1.43 to 3.26; P:=0.0003) and cardiac mortality (hazard ratio, 2.38; 95% CI, 1.48 to 3.85; P:=0.0004). CONCLUSIONS: This study demonstrates that restenosis, especially in its occlusive form, is a major determinant of long-term mortality in diabetic patients after coronary balloon angioplasty.

Effect of percutaneous adenovirus-mediated Gax gene delivery to the arterial wall in double-injured atheromatous stented rabbit iliac arteries.

Though the efficacy of intravascular gene transfer has been demonstrated in native vessels following acute injury, this methodology has not been validated in complex models of vascular injury that more closely mimic clinical angioplasty procedures. Previous studies have shown that Gax gene overexpression modulates the injury-induced remodeling of the vessel in rat carotid and normal rabbit iliac arteries. Here, we evaluated the effect of the Gax gene delivery in atheromatous stented vessels. Rabbits were fed 120 g daily of 1% cholesterol diet for 3 weeks. At 1 week they underwent initial injury on the external iliac artery, then balloon angioplasty was performed at 3 weeks at the same site with a 2.5 mm diameter channel balloon catheter (three times 1 min at 6 atm). Either saline (n = 4) or the control viral construct Ad-CMVluc (5 x 109 p.f.u.) (n = 5) or Ad-CMVGax (5 x 10(9) p.f.u.) (n = 4) was delivered with a poloxamer mixture via a channel balloon (6 atm, 30 min), and a 15 mm long Palmaz-Schatz stent (PS154) was then deployed at the site (1 min, 8 atm). Arteries were analyzed 1 month later. At 1 month, the Ad-CMVGax treated arteries exhibited a lower maximal intimal area (1. 15+/-0.1 mm2) than saline (1.87+/-0.15 mm2, P = 0.007) or Ad-CMVluc-treated vessels (1.98+/-0.31 mm2, P = 0.04). Likewise Ad-CMVGax-treated vessels displayed a lower maximal percentage cross-sectional area narrowing (35.1+/-3.5%) than saline (65.3+/-9.4%, P = 0.01) or Ad-CMVluc-treated vessels (62.7+/-6.7%, P = 0.02). Angiographic analysis revealed larger minimal lumen diameter in Ad-CMVGax treated arteries (2.0+/-0.1 mm) than saline (1.14+/-0.36 mm, P = 0.06) or Ad-CMVluc-treated vessels (1.23+/-0.25 mm, P = 0.02). Overexpression of the Gax gene inhibits neointimal hyperplasia and lumen loss in atheromatous stented rabbit iliac arteries.