Sidney Cohen

Long-Term Results of Carotid Stenting versus Endarterectomy in High-Risk Patients

BACKGROUND We previously reported that, in a randomized trial, carotid stenting with the use of an emboli-protection device is not inferior to carotid endarterectomy for the treatment of carotid artery disease at 30 days and at 1 year. We now report the 3-year results. METHODS The trial evaluated carotid artery stenting with the use of an emboli-protection device as compared with endarterectomy in 334 patients at increased risk for complications from endarterectomy who had either a symptomatic carotid artery stenosis of at least 50% of the luminal diameter or an asymptomatic stenosis of at least 80%. The prespecified major secondary end point at 3 years was a composite of death, stroke, or myocardial infarction within 30 days after the procedure or death or ipsilateral stroke between 31 days and 1080 days (3 years). RESULTS At 3 years, data were available for 260 patients (77.8%), including 85.6% of patients in the stenting group and 70.1% of those in the endarterectomy group. The prespecified major secondary end point occurred in 41 patients in the stenting group (cumulative incidence, 24.6%; Kaplan-Meier estimate, 26.2%) and 45 patients in the endarterectomy group (cumulative incidence, 26.9%; Kaplan-Meier estimate, 30.3%) (absolute difference in cumulative incidence for the stenting group, -2.3%; 95% confidence interval, -11.8 to 7.0). There were 15 strokes in each of the two groups, of which 11 in the stenting group and 9 in the endarterectomy group were ipsilateral. CONCLUSIONS In our trial of patients with severe carotid artery stenosis and increased surgical risk, no significant difference could be shown in long-term outcomes between patients who underwent carotid artery stenting with an emboli-protection device and those who underwent endarterectomy. (ClinicalTrials.gov number, NCT00231270 [ClinicalTrials.gov].).

Five-Year Follow-Up After Sirolimus-Eluting Stent Implantation : Results of the SIRIUS (Sirolimus-Eluting Stent in De-Novo Native Coronary Lesions) Trial

OBJECTIVES The aim of this study was to examine the 5-year clinical safety and efficacy outcomes in patients enrolled in the SIRIUS (Sirolimus-Eluting Stent in De-Novo Native Coronary Lesions) trial. BACKGROUND The SIRIUS trial was a double-blinded randomized study that demonstrated that sirolimus-eluting stents (SES) significantly improved angiographic results (at 8 months) and clinical outcomes (at 9 and 12 months) compared with bare-metal stents (BMS). METHODS Patients (n = 1,058) with de novo native coronary artery lesions were randomized to either SES (n = 533) or control BMS (n = 525) and were followed for 5 years. RESULTS Between 1 and 5 years, additional clinical events were similarly distributed among the sirolimus and control groups. At 5 years, in sirolimus versus control patients, target lesion revascularization was 9.4% versus 24.2% (p < 0.001) and major adverse cardiovascular events and target vessel failure rates were 20.3% versus 33.5% and 22.5% versus 33.5%, respectively (p < 0.0001 for both). There were no significant differences in death, myocardial infarction, and nontarget lesion revascularization. No significant differences were observed in the cumulative incidence of stent thrombosis for sirolimus versus control patients with either protocol-derived (1.0% vs. 0.8%) or Academic Research Consortium definitions (3.9% vs. 4.2%). CONCLUSIONS In patients with noncomplex coronary artery disease, clinical outcomes 5 years after implantation of SES continue to demonstrate significant reduction in the need for repeat revascularization, with similar safety (death and myocardial infarction) compared with BMS, without evidence for either disproportionate late restenosis or late stent thrombosis.

Pneumatic Dilatation or Esophagomyotomy Treatment for Idiopathic Achalasia: Clinical Outcomes and Cost Analysis

The choice between pneumatic dilatation and surgical esophagomyotomy as the initial treatment for achalasia is controversial. The aims of this study were to determine the long term clinical outcome and costs of treating achalasia initially with pneumatic dilatation as compared to esophagomyotomy. Of 123 patients undergoing an initial pneumatic dilatation for achalasia at our institution from 1976 to 1986, 71 (58%) received no further treatment for achalasia during a mean follow up of 4.7±2.8 years. Only 15 of these 123 patients (12%) eventually underwent surgical esophagomyotomy, (two for perforation during pneumatic dilatation, 13 for persistent or recurrent symptoms). The degree of dysphagia at follow up was improved to a similar degree in patients treated with an initial pneumatic dilatation as compared to patients treated with an initial esophagomyotomy. Patients with age≥45, years at time of initial pneumatic dilatation had fewer subsequent treatments for persistent or recurrent symptoms and had less dysphagia on follow up as compared to patients <45 years. Subsequent pneumatic dilatations to treat persistent or recurrent symptoms were less beneficial than an initial pneumatic dilation. The cost of esophagomyotomy was 5 times greater than the cost of pneumatic dilatation. When costs were analyzed to include subsequent treatments of symptomatic patients, the total expectant costs of treating with an initial esophagomyotomy remained 2.4 times greater than treating with an initial pneumatic dilatation. This study suggests that an initial pneumatic dilatation will be the only treatment needed for the majority of patients with achalasia. A treatment regimen starting with penumatic dilatation has less overall costs than starting with esophagomyotomy. For each subsequent pneumatic dilatation, however, the clinical benefit leans toward, surgery.

Evaluation of the Time Saved by Prehospital Initiation of Reteplase for ST-Elevation Myocardial Infarction Results of the Early Retavase-Thrombolysis In Myocardial Infarction (ER-TIMI) 19 Trial

OBJECTIVES The Early Retavase-Thrombolysis In Myocardial Infarction (ER-TIMI) 19 trial tested the feasibility of prehospital initiation of the bolus fibrinolytic reteplase (rPA) and determined the time saved by prehospital rPA in the setting of contemporary emergency cardiac care. BACKGROUND Newer bolus fibrinolytics have undergone only limited evaluation for prehospital administration. In addition, as door-to-drug times have decreased, the relevance of findings from prior trials of prehospital fibrinolysis has become less certain. METHODS Patients (n = 315) with ST-elevation myocardial infarction (STEMI) were enrolled in 20 emergency medical systems in North America. The time from emergency medical service (EMS) arrival to administration of a fibrinolytic was compared between study patients receiving prehospital rPA and sequential control patients from 6 to 12 months before the study who received a fibrinolytic in the hospital. RESULTS Acute myocardial infarction was confirmed in 98%. The median time from EMS arrival to initiation of rPA was 31 min (25th to 75th percentile, 24 min to 37 min). The time from EMS arrival to in-hospital fibrinolytic for 630 control patients was 63 min (25th to 75th percentile, 48 min to 89 min), resulting in a time saved of 32 min (p < 0.0001). By 30 min after first medical contact, 49% of study patients had received the first bolus of fibrinolytic compared with only 5% of controls (p < 0.0001). In-hospital mortality was 4.7%. Intracranial hemorrhage occurred in 1.0%. CONCLUSIONS Prehospital administration of rPA is a feasible approach to accelerating reperfusion in patients with STEMI. Valuable time savings can be achieved in the setting of contemporary transport and door-to-drug times and may translate into an improvement in clinical outcomes.

Immunocytochemical Localization of rH1 Sodium Channel in Adult Rat Heart Atria and Ventricle Presence in Terminal Intercalated Disks

BACKGROUND Of the five sodium channel subtypes expressed in cardiac tissues, the rat (rH1) and human (hH1) isoforms are thought to be the predominant subtypes on the basis of heterologous expression studies. In this study, subtype-specific antibodies and immunocytochemistry were used to confirm protein expression and to localize rH1 protein in cardiac tissues. METHODS AND RESULTS Subtype-specific antibodies immunolabeled adult rat heart tissue in a manner identical to that obtained with subtype-nonselective antibodies. All antibodies specifically bound to the surface and t-tubular systems of atrial and ventricular muscle cells. Cytoplasmic labeling, reflecting nascent sodium channels or cytoplasmic stores of sodium channel protein, was apparent. Most notably, all antibodies also specifically labeled the subset of intercalated disks located at the ends but not the sides of adjacent ventricular muscle cells. CONCLUSIONS rH1 is the predominant subtype expressed on rat atrial and ventricular muscle cells. rH1 protein localization in surface and t-tubular membranes is consistent with its proposed role in coordinating membrane depolarization along the length and deep within cardiac muscle cells. rH1 protein localization in terminal intercalated disks suggests that sodium channels may also act as a localized voltage-dependent current amplifier, raising the safety margin for conduction; they also may contribute to anisotropic or saltatory conduction in cardiac tissues. These electrophysiological properties would be particularly important under conditions of altered, channel function resulting from ion channel gene defects (e.g., long QT syndrome), antiarrhythmic drug therapy, ischemia, or other heart diseases by influencing the electrophysiological substrate for ventricular tachyarrhythmias.

Carotid artery stenting with emboli protection surveillance study: thirty-day results of the CASES-PMS study.

Objective: This study examined whether physicians with varying carotid stent experience would obtain safety and efficacy outcomes as good as those from the pivotal SAPPHIRE trial following participation in a comprehensive carotid stent training program. Background: This study was performed as a condition of approval study for the PRECISE® Nitinol Stent and the ANGIOGUARD™ XP Emboli Capture Guidewire. Methods: Patients at high surgical risk who were either symptomatic with ≥50% stenosis or asymptomatic with ≥80% stenosis of the common or internal carotid artery received carotid artery stenting with distal emboli protection using the PRECISE Nitinol Stent and the ANGIOGUARD XP Emboli Capture Guidewire. Physicians were qualified based on either prior experience in carotid stenting with the ANGIOGUARD XP Emboli Capture Guidewire or following participation in a formal training program. The primary endpoint of major adverse events (MAE) at 30 days (death, myocardial infarction (MI), or stroke) was tested for noninferiority compared with an objective performance criterion (OPC) of 6.3% established from the stent cohort of the SAPPHIRE trial. Results: The 30‐day MAE rate was 5.0%, meeting the criteria for noninferiority to the prespecified OPC (95% CI [3.9%, 6.2%] P < 0.001). Asymptomatic patients (N = 1,158, 78.2%) had similar outcomes to the overall results (MAE 4.7%). Outcomes were similar across levels of physician experience, carotid stent volume, geographic location, presence/absence of training program. Conclusions: Utilizing a comprehensive training program, carotid artery stenting by operators with differing experience in a variety of practice settings yielded safety and efficacy outcomes similar to those reported in the SAPPHIRE trial.

Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised, sham-controlled, proof-of-concept trial

BACKGROUND Previous randomised renal denervation studies did not show consistent efficacy in reducing blood pressure. The objective of our study was to evaluate the effect of renal denervation on blood pressure in the absence of antihypertensive medications. METHODS SPYRAL HTN-OFF MED was a multicentre, international, single-blind, randomised, sham-controlled, proof-of-concept trial. Patients were enrolled at 21 centres in the USA, Europe, Japan, and Australia. Eligible patients were drug-naive or discontinued their antihypertensive medications. Patients with an office systolic blood pressure (SBP) of 150 mm Hg or greater and less than 180 mm Hg, office diastolic blood pressure (DBP) of 90 mm Hg or greater, and a mean 24-h ambulatory SBP of 140 mm Hg or greater and less than 170 mm Hg at second screening underwent renal angiography and were randomly assigned to renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were blinded to randomisation assignments. The primary endpoint, change in 24-h blood pressure at 3 months, was compared between groups. Drug surveillance was done to ensure patient compliance with absence of antihypertensive medication. The primary analysis was done in the intention-to-treat population. Safety events were assessed at 3 months. This study is registered with ClinicalTrials.gov, number NCT02439749. FINDINGS Between June 25, 2015, and Jan 30, 2017, 353 patients were screened. 80 patients were randomly assigned to renal denervation (n=38) or sham control (n=42) and followed up for 3 months. Office and 24-h ambulatory blood pressure decreased significantly from baseline to 3 months in the renal denervation group: 24-h SBP -5·5 mm Hg (95% CI -9·1 to -2·0; p=0·0031), 24-h DBP -4·8 mm Hg (-7·0 to -2·6; p<0·0001), office SBP -10·0 mm Hg (-15·1 to -4·9; p=0·0004), and office DBP -5·3 mm Hg (-7·8 to -2·7; p=0·0002). No significant changes were seen in the sham-control group: 24-h SBP -0·5 mm Hg (95% CI -3·9 to 2·9; p=0·7644), 24-h DBP -0·4 mm Hg (-2·2 to 1·4; p=0·6448), office SBP -2·3 mm Hg (-6·1 to 1·6; p=0·2381), and office DBP -0·3 mm Hg (-2·9 to 2·2; p=0·8052). The mean difference between the groups favoured renal denervation for 3-month change in both office and 24-h blood pressure from baseline: 24-h SBP -5·0 mm Hg (95% CI -9·9 to -0·2; p=0·0414), 24-h DBP -4·4 mm Hg (-7·2 to -1·6; p=0·0024), office SBP -7·7 mm Hg (-14·0 to -1·5; p=0·0155), and office DBP -4·9 mm Hg (-8·5 to -1·4; p=0·0077). Baseline-adjusted analyses showed similar findings. There were no major adverse events in either group. INTERPRETATION Results from SPYRAL HTN-OFF MED provide biological proof of principle for the blood-pressure-lowering efficacy of renal denervation. FUNDING Medtronic.

Esophageal chest pain: value of high-dose provocative testing with edrophonium chloride in patients with normal esophageal manometries

The unequivocal diagnosis of esophageal chest pain requires the demonstration of simultaneous manometric changes and chest pain. Numerous provocative agents have been used to enhance the diagnostic value of esophageal manometry. Our aims were to: (1) evaluate consecutively a large group of patients with proven noncardiac chest pain and normal baseline manometric studies, using edrophonium chloride, 10 mg, and (2) determine the value of provocative testing in clinical practice. One hundred twenty patients with normal standard baseline esophageal manometries were studied using blinded testing with edrophonium chloride and followed clinically by questionnaire. A positive response of both chest pain and manometric changes was observed in 34%, a negative response in 49%, and an indeterminate response in 17% of patients. Baseline manometric features, including high-amplitude contractions, did not predict the response to edrophonium chloride. Following edrophonium chloride administration, the change in amplitude, duration, and number of repetitive contractions from baseline was significantly greater in positive responders. Edrophonium decreased the velocity of propagated contractions in positive responders (P<0.05), but not in nonresponders. Response to edrophonium chloride could not be predicted by patient age, sex, or clinical symptomatology. Seventy percent of patients in both groups had symptoms indistinguishable from ischemic heart disease. After making a specific diagnosis of esophageal chest pain, patients showed a marked clinical improvement, with a significant decrease in physical limitation, emergency room visits, hospital and CCU admissions, and in further cardiac testing. We conclude that provocative testing with edrophonium chloride will make it possible to definitively implicate the esophagus in over 30% of patients with normal baseline manometric findings and noncardiac chest pain.

The Jonas Study: Evaluation of the Retrievability of the Cordis OptEase Inferior Vena Cava Filter

PURPOSE To evaluate the success, safety, and efficacy of the retrieval of the OptEase Permanent/Retrievable Vena Cava Filter (Cordis, Warren, NJ), when implanted for temporary protection against venous thromboembolism. MATERIALS AND METHODS This prospective, multicenter, non-randomized study enrolled 27 patients who needed temporary protection against pulmonary embolism in whom the intent at the time of filter insertion was retrieval of the OptEase filter. Patients presented with deep venous thrombosis (n = 17), pulmonary embolism (PE) (n = 6), and high risk for PE without thromboembolic disease (n = 4). Assessments included duplex sonography of the access site performed within 24 hours of device implantation and retrieval. All patients underwent cavography before and after filter placement and filter retrieval. Contrast-enhanced computed tomography (CT) of the abdomen and clinical follow-up was performed at 1 month after device retrieval. RESULTS Of the 27 enrolled patients, 21 patients (77.8%) met the criteria for retrieval and all 21 patients (100%) had filters successfully retrieved with no associated adverse events. Retrieval was not attempted in six patients as a result of ongoing contraindication to anticoagulation (n = 3), large trapped thrombi within the filter (n = 2), and poor patient prognosis (n = 1). Time to retrieval ranged from 5 to 14 days with a mean implantation time of 11.1 days +/- 1.82. No symptomatic pulmonary embolism, vena cava wall injury, vena cava stenosis, significant bleeding, filter fracture, or filter migration was observed. Nineteen of the 21 patients (90.5%) were followed for 1-month post-retrieval with no device-related adverse events or symptomatic PE. Caval patency was documented in 18 of these 19 patients with CT. Two patients were lost to follow-up, and one patient refused to undergo CT examination. CONCLUSION The OptEase permanent/retrievable vena cava filter can be safely and successfully retrieved up to 14 days in patients who no longer require inferior vena cava filter protection against pulmonary embolism.

Human colonic myoelectric activity in response to prostigmin and the gastrointestinal hormones.

Colonic myoelectric activity was determined using a mucosal clip electrode in normal human subjects, in the basal state and following the administration of prostigmin, pentagastrin, cholecystokinin, or secretin. Slow-wave activity was present 49±3.0% of the recording time and occurred at two frequencies, 6.5±0.1 cycles/min and 3.5±0.1 cycles/min, in the rectum. Spike potentials were infrequent in the basal state. Prostigmin, pentagastrin, or cholecystokinin did not affect the slow-wave activity or frequency, but these agents significantly increased the number of spike potentials (P<0.05). Secretin had no effect on myoelectric activity. The electrode system was tested in the cat and showed excellent correlation of the myoelectric activity between the mucosal clip electrode and a serosal electrode. These studies indicate: (1) a mucosal clip electrode provides an accurate method of recording colonic myoelectric activity when compared to a serosal electrode in the cat; (2) in man, slow-wave activity is present only intermittently and exists at two frequencies, approximately 6 cycles/min and 3 cycles/min; (3) gastrointestinal hormones and prostigmin increase spike potential discharge without altering slow-wave activity or frequency.