Paul Kramer

Percutaneous Left Atrial Appendage Transcatheter Occlusion to Prevent Stroke in High-Risk Patients With Atrial Fibrillation Early Clinical Experience

Background—Thromboembolism due to atrial fibrillation (AF) is a frequent cause of stroke. More than 90% of thrombi in AF form in the left atrial appendage (LAA). Obliteration of the appendage may prevent embolic complications. Methods and Results—We evaluated the feasibility and safety of implanting a novel device for percutaneous left atrial appendage transcatheter occlusion (PLAATO). LAA occlusion using the PLAATO system was attempted in 15 patients with chronic AF at high risk for stroke, who are poor candidates for long-term warfarin therapy. The implant consists of a self-expanding nitinol cage covered with a polymeric membrane (ePTFE). The LAA was successfully occluded in 15/15 patients (100%). Angiography and transesophageal echocardiography (TEE) during the procedure showed that the device was well-seated in all patients and that there was no evidence of perforation, device embolization, or interference with surrounding structures. In 1 patient, the first procedure was complicated by a hemopericardium, which occurred during LAA access. A second attempt 30 days later was successful with no untoward sequela. No other complications occurred. At 1-month follow-up, chest fluoroscopy and TEE revealed continued stable implant position with smooth atrial-facing surface and no evidence of thrombus. Conclusions—Thus, transcatheter closure of the LAA is feasible in humans. This novel implant technology may be appropriate for patients with AF who are not suitable candidates for anticoagulation therapy. Further trials are needed to show the long-term safety and its efficacy in reducing stroke.

Percutaneous Left Atrial Appendage Occlusion for Patients in Atrial Fibrillation Suboptimal for Warfarin Therapy: 5-Year Results of the PLAATO (Percutaneous Left Atrial Appendage Transcatheter Occlusion) Study

OBJECTIVES The aim of this study was to determine 5-year clinical status for patients treated with percutaneous left atrial appendage transcatheter occlusion with the PLAATO (Percutaneous Left Atrial Appendage Transcatheter Occlusion) system. BACKGROUND Anticoagulation reduces thromboembolism among patients with nonvalvular atrial fibrillation (AF). However, warfarin is a challenging medication due to risks of inadequate anticoagulation and bleeding. Thus, PLAATO was evaluated as a treatment strategy for nonwarfarin candidate patients with AF at high risk for stroke. METHODS Sixty-four patients with permanent or paroxysmal AF participated in this observational, multicenter prospective study. Primary end points were: new major or minor stroke, cardiac or neurological death, myocardial infarction, or requirement for cardiovascular surgery related to the procedure within 1 month of the index procedure. Patients were followed for up to 5 years. RESULTS Thirty-day freedom from major adverse events rate was 98.4% (95% confidence interval: 90.89% to >99.99%). One patient, who did not receive a PLAATO implant, experienced 2 events within 30 days (cardiovascular surgery, death). Treatment success was 100% 1 month after device implantation. At 5-year follow-up, there were 7 deaths, 5 major strokes, 3 minor strokes, 1 cardiac tamponade requiring surgery, 1 probable cerebral hemorrhage/death, and 1 myocardial infarction. Only 1 event (cardiac tamponade) was adjudicated as related to the implant procedure. After up to 5 years of follow-up, the annualized stroke/transient ischemic attack (TIA) rate was 3.8%. The anticipated stroke/TIA rate (with the CHADS(2) scoring method) was 6.6%/year. CONCLUSIONS The PLAATO system is safe and effective. At 5-year follow-up the annualized stroke/TIA rate in our patients was 3.8%/year, less than predicted by the CHADS(2) scoring system.

Effect of percutaneous mitral repair with the MitraClip ® device on mitral valve area and gradient

AIMS Percutaneous repair of mitral regurgitation (MR) by leaflet apposition using a clip deployed via transseptal catheterisation is undergoing evaluation. METHODS AND RESULTS In order to detect the potential for clinically significant left ventricular inflow obstruction after percutaneous repair, we measured mitral valve area (MVA) and mean transmitral gradient (MVG) echocardiographically in 96 patients implanted with a clip followed for up to 24 months. By planimetry, the mean MVA decreased from 6.0 +/- 1.3 cm2 to 3.6 +/- 1.2 cm2 (p < 0.05) (range 1.9 to 7.6 cm2) after clip placement, and remained unchanged after 24 months of follow-up (3.5 +/- 0.8 cm2). The mean MVG increased after clip placement from 1.7 +/- 0.9 mmHg to 4.1 +/- 2.2 mmHg (p < 0.05), and did not increase further to 24 months (3.8 +/- 1.9 mmHg). There were no differences in MVA or MVG between patients who received 1-clip (69%) and those receiving 2-clips (31%). Patients with functional MR (23%) had a slightly smaller MVA, both at baseline and after clip placement, but did not differ from degenerative MR patients at later follow-up. After 2 years of follow-up, no patient required surgery for LV inflow obstruction. CONCLUSIONS Mitral repair with the MitraClip device for MR decreases MVA without significant mitral obstruction. After 2 years of follow-up, no patient required surgery for LV inflow obstruction, and these results were not influenced by the use of more than 1 clip or the aetiology of MR.

Photoangioplasty for Human Peripheral Atherosclerosis Results of a Phase I Trial of Photodynamic Therapy With Motexafin Lutetium (Antrin)

BackgroundIn photoangioplasty, light activation of a photosensitive drug offers the potential for treatment of long segments of vascular disease. This is a brief description of a study designed to evaluate the safety and tolerability of a new photosensitizer, Antrin (motexafin lutetium), in the endovascular treatment of atherosclerosis. Methods and ResultsAn open-label, single-dose, escalating drug- and light-dose study was performed in patients with atherosclerotic peripheral arterial insufficiency. Clinical evaluation, serial quantitative angiography, and intravascular ultrasonography were performed. Therapy was well tolerated, and only minor side effects were observed. Treatment produced no deleterious vascular effects. Although this study was not designed to examine clinical efficacy, several secondary end points suggested a favorable therapeutic effect. ConclusionsThis phase I study demonstrates that photoangioplasty with motexafin lutetium is well tolerated and safe. Preliminary efficacy data suggest a future role for the treatment of flow-limiting atherosclerosis.

Phase I Drug and Light Dose-Escalation Trial of Motexafin Lutetium and Far Red Light Activation (Phototherapy) in Subjects With Coronary Artery Disease Undergoing Percutaneous Coronary Intervention and Stent Deployment Procedural and Long-Term Results

Background—Motexafin lutetium (MLu; Antrin) is a photosensitizer that is taken up by atherosclerotic plaque and concentrated within macrophages and vascular smooth muscle cells. After photoactivation with far red light, MLu facilitates production of cytotoxic oxygen radicals that mediate apoptosis. We assessed the safety and tolerability of phototherapy (PT) with MLu in patients undergoing percutaneous coronary intervention with stent deployment. Methods and Results—An open-label, phase I, drug and light dose-escalation clinical trial of MLu PT enrolled 80 patients undergoing de novo coronary stent deployment. MLu was administered to 79 patients by intravenous infusion 18 to 24 hours before procedure, and photoactivation was performed after balloon predilatation and before stent deployment. Clinical evaluation, serial quantitative angiography, and intravascular ultrasound were performed periprocedurally and at 6 months follow-up. MLu PT was well tolerated without serious dose-limiting toxicities, and side effects (paresthesia and rash) were minor. No adverse angiographic outcomes were attributed to phototherapy. Conclusions—This study demonstrates that coronary MLu PT seems safe, and the maximum well-tolerated MLu dose and range of tolerated light doses were identified. These data can be used in phase II efficacy trials of MLu PT for the treatment of coronary atherosclerosis or vulnerable plaque.

iCoapsys mitral valve repair system: Percutaneous implantation in an animal model.

Objective: Determine if the iCoapsys device could be accurately and safely implanted using a novel transcatheter system. Background: Functional mitral regurgitation is a ventricular disease characterized by mitral insufficiency in the absence of structural valve abnormalities. It occurs in the presence of ischemic or non‐ischemic cardiomyopathy. The Coapsys (surgical) transventricular device, currently undergoing randomized evaluation, offers a more integrated treatment strategy. Methods: The iCoapsys transcatheter mitral valve repair system was developed for percutaneous delivery of an implant designed to emulate the surgical (i.e. Coapsys) device. Nine operators tested the ability of this novel catheter system to successfully deliver and position the iCoapsys implant in 12 adult sheep. Results: Post mortem evaluation in this acute model demonstrated precise percutaneous delivery and implantation in all 12 animals using fluoroscopic, coronary angiographic, and epicardial echo guidance. There was no excessive bleeding, hemodynamic compromise or sustained arrhythmias. Conclusions: A novel transcatheter methodology was developed to consistently deliver and accurately position the iCoapsys implant. The percutaneous iCoapsys system was successfully implanted without complication in this acute animal model series.

Long-term follow-up of the Starflex device for closure of secundum atrial septal defect

There is limited published outcome data on the STARFlex® device for transcatheter closure of atrial septal defects (ASD).

On horse sense and horse feathers: an argument against insistence on enrolling cryptogenic stroke patients with patent foramen ovale in randomized clinical trials.

I have been asked to write the antagonist’s argument related to the proposition that all patients undergoing percutaneous device closure of patent foramen ovale for prevention of recurrent neurological events due to presumed paradoxical embolism should be enrolled in a randomized clinical trial. Arguing against such enrollment is a bit like arguing against world peace. There can be little doubt that completion of the randomized trials currently underway would result in powerful medical evidence upon which broad consensus could be achieved regarding management of patients with cryptogenic stroke and PFO and so what is the basis for a debate? Simply complete the trials, submit the data to the FDA, and await regulatory approval if the trials indicate sufficient safety and efficacy. No problem! Actually, there are several problems. Chief among these is the failure of the randomized trials initiated to date to enroll at a rate that would encourage any optimism that they will proceed to completion. About nine years ago, a small, FDA-approved randomized trial of the Clamshell device enrolled fewer than ten patients. The subsequent attempt at a trial, in which the number of sites was expanded to about ten and involved CardioSEAL as the successor to Clamshell, enrolled eleven patients by eighteen months. About three years ago, much larger and far more ambitious trials were undertaken at a time when there was a broad awareness of the association of cryptogenic stroke with PFO, the number of interventional cardiologists with solid clinical experience in PFO closure had increased dramatically, and the appreciation of the need for and availability of funding for such trials seemed optimal for rapid enrollment. Unfortunately, history has repeated itself. The most successful of the three trials currently underway is only 20% enrolled, despite intensive encouragement by the sponsor, sincerely expressed commitments by the investigators, and the FDA’s insistence that it will not consider any alternative to such trials as a pathway to market approval. At this rate, and only assuming the ability to maintain current rates of enrollment, trial completion can be anticipated no sooner than the year 2017. If so, is continued conduct of, let alone mandatory referral of patients into, these trials in the best interest of the public? There are many factors contributing to the failure of these randomized trials to enroll, and not all of them are sinister. The biggest single factor is the fact that clinical trials related to cryptogenic stroke and percutaneous PFO closure were formulated after closure devices were already commercially available. 1988 saw the first published reports of the association of PFO and stroke. The next few years saw anecdotal reports of very low recurrence rates when such patients were treated with surgical or device closure. Growing interest among neurologists and cardiologists in such treatment paralleled the evolution of the Clamshell and CardioSEAL devices from one manufacturer and the PFO and Atrial Septal Occluders from another. During this time, the regulatory environment did not foreclose the development of referral patterns for and clinical expertise in percutaneous defect closure. In February of 2000, the FDA granted Humanitarian Device Exemption for PFO closure devices from both companies, further expanding the landscape in which defect closure could be performed. It was about 15 months later when the three current trials got underway. By that time, it was common practice in many medical communities to refer patients with cryptogenic stroke and PFO to centers where the defects could be closed percutaneously. Commercial insurance rarely contested reimbursement for these procedures. The emotional

SECOND HARMONIC IMAGING : GOOD REVERBERATIONS

contrast-containing structures can be amplified while spurious fundamental-frequency signals from the near field and from side lobes can be virtually eliminated. Tissue second harmonic imaging differs from contrast imaging in that reverberations are not responsible for generation of the harmonic signal. As the fundamental signal penetrates the chest and travels through extracardiac and then cardiac tissue, the pressure wave results in infinitesimal compression and decompression of water. The resulting slight variations in water density result in altered wave transmission and the creation of low-intensity harmonics. The strength of these harmonic signals is related to the intensity and frequency of the fundamental signal.7,8 Weak, spurious signals from side lobes or the chest wall contain very weak harmonic signals so that when signal filtering selects out the harmonic frequency, these sources of artifact are greatly reduced. In addition, there is an accumulation of the harmonic frequency at increasing depths from the transducer. At the chest wall, there is a negligible component of locally produced second harmonic frequency. At increasing depths, however, more and more tissue generates second harmonic frequency that becomes a greater portion of the reflected signal. When the return signal is filtered to the second harmonic and amplified, the signal-to-noise ratio is greatly enhanced. In this issue of the Journal, Senior et al9 add convincingly to the growing body of information that second harmonic imaging greatly enhances the echocardiographic image in patients determined to have poor endocardial delineation when imaged at fundamental frequency. This simple but elegant study demonstrates, in all 4 conventional views, a highly significant reduction of the numbers of segments with poor endocardial depiction with harmonic imaging. As a result, assessment of segmental wall thickening was also significantly enhanced. Such findings naturally suggest an angiographic correlation study of stress echocardiography with fundamental versus harmonic imaging. One of the principle limitations of stress echocardiography has been incomplete segmental endocardial definition and, therefore, impaired interpretability of regional wall thickening. In an era of increasingly limited resources, cardiac ultrasound continues to grow in its ability to assess all manner of cardiovascular disease. The amount of information that can be obtained relating to myocardial, pericardial, valvular, congenital, and coronary heart disease increases incrementally with each enhancement of technique and technology. The amount of detailed information that can Second harmonic imaging: Good reverberations

Comparison of results of coronary angioplasty during acute myocardial infarction with and without previous coronary bypass surgery

Six hundred one consecutive patients undergoing reperfusion within 6 hours of acute myocardial infarction were studied with regard to impact of previous coronary artery bypass grafting (CABG) on direct coronary angioplasty performance and results. Forty-nine patients (8%) had previously undergone CABG, whereas 552 (92%) had not. Direct angioplasty was used for reperfusion in 35 patients (71%) in the CABG group, and in 258 (47%) in the non-CABG group (p < 0.01). No significant differences between these groups were noted with regard to gender, age, infarction site, time to reperfusion or angioplasty success (34 of 35 CABG patients [97%] vs 236 of 258 non-CABG patients [92%]). CABG patients were more likely to have had previous infarction (17 of 35 [49%] vs 35 of 258 [14%] [p < 0.001]), multivessel disease (34 of 35 [97%] vs 127 of 258 [49%] [p < 0.001]) and lower mean ejection fraction (0.36 +/- 0.13 vs 0.46 +/- 0.12, p < 0.001). Over a mean follow-up of 151 weeks, 24 patients (69%) in the CABG group were restudied versus 112 (43%) in the non-CABG group (p < 0.01). Restenosis occurred in 14 patients (40%) in the CABG group versus 58 (22%) in the group without previous CABG (p = 0.04). In the CABG group, restenosis occurred significantly more often in saphenous vein grafts than in native vessels (12 of 17 [71%] vs 2 of 11 [18%] [p < 0.02]). There was no significant difference in the overall performance of repeat angioplasty between the 2 groups.(ABSTRACT TRUNCATED AT 250 WORDS)