Compiled by EPLabDigest

Compiled by EPLabDigest

FDA Approves Xarelto to Prevent Stroke in People With Common Type of Abnormal Heart Rhythm

The U.S. Food and Drug Administration approved the anti-clotting drug Xarelto (rivaroxaban) to reduce the risk of stroke in people who have abnormal heart rhythm (non-valvular atrial fibrillation).

Atrial fibrillation occurs in more than 2 million Americans and is one of the most common types of abnormal heart rhythm. In atrial fibrillation, the beating of the heart’s two upper heart chambers is irregular and poorly coordinated. This leads to blood pooling in these chambers, resulting in blood clots. Non-valvular atrial fibrillation refers to atrial fibrillation in patients who do not have significant problems in their heart valves.

“Atrial fibrillation can lead to the formation of blood clots, which can travel to the brain, blocking blood flow and causing a disabling stroke,” said Norman Stockbridge, MD, PhD, director of the Division of Cardiovascular and Renal Products in the FDA’s Center for Drug Evaluation and Research. “This approval gives doctors and patients another treatment option for a condition that must be managed carefully.”

A stroke occurs if the flow of blood to a portion of the brain is blocked. If brain cells die or are damaged because of a stroke, symptoms occur in the parts of the body that these brain cells control. Stroke symptoms include sudden weakness; paralysis or numbness of the face, arms, or legs; trouble speaking or understanding speech; and trouble seeing.

The safety and efficacy of Xarelto were evaluated in a clinical trial with more than 14,000 patients comparing Xarelto with the anti-clotting drug warfarin. In the trial, Xarelto was similar to warfarin in its ability to prevent stroke.

For people taking the drug for atrial fibrillation, Xarelto should be taken one time a day with the evening meal so that it will be completely absorbed. 

As with other anti-clotting drugs, Xarelto can cause bleeding that, rarely, can lead to death. Bleeding was the most common adverse event reported by patients treated with Xarelto in the major clinical trial for the prevention of stroke in non-valvular atrial fibrillation. In that trial, Xarelto’s risk of major bleeding was similar to that of warfarin; however, it caused less bleeding into the brain and more bleeding into the stomach and intestines.

Xarelto has a boxed warning to make clear that people using the drug should not discontinue it before talking with their health care professional. Discontinuing the drug can increase the risk of stroke.

An FDA-required Medication Guide, which will be given to patients and caregivers when Xarelto is dispensed, describes the risks and adverse reactions people should be mindful of when using the drug.

Xarelto is marketed in the United States by Titusville, N.J.-based Janssen Pharmaceuticals Inc.

On July 1, 2011, the FDA approved Xarelto to reduce the risk of blood clots, deep vein thrombosis, and pulmonary embolism following knee or hip replacement surgery.

Boston Scientific’s WATCHMAN® Device Implanted in First Patients in Latin America

Boston Scientific Corporation’s WATCHMAN® Left Atrial Appendage (LAA) Closure Device has been implanted in the first patients in Latin America. The novel device is designed for use in patients in atrial fibrillation who are at risk for stroke and are eligible for long-term oral anticoagulation therapy such as warfarin. The WATCHMAN LAA Closure Device is intended to prevent embolization of thrombi that may form in the LAA, thereby preventing the occurrence of ischemic stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation. The first patient implants were performed by Bernardo Caicedo, MD, Interventional Cardiologist, at Angiografia de Occidente in Cali, Colombia.

Patients in atrial fibrillation are at greater risk for stroke due to the formation and migration of clots in the left atrial appendage. Anticoagulants such as warfarin have traditionally been the only therapy for reducing stroke risk in these patients. Boston Scientific’s WATCHMAN device is intended to be an alternative to long-term anticoagulation. It is designed to close the LAA, thereby preventing clots within the appendage from being dislodged into the bloodstream.

“I am excited to be part of the first patient implants of the WATCHMAN device in Latin America,” said Dr. Caicedo. “The percutaneously delivered device promises to offer a safe and effective alternative for atrial fibrillation patients who cannot take long-term oral anticoagulants and have limited options to reduce their stroke risk. It incorporates a pre-loaded device that is both repositionable and retrievable to enhance its ease of use.”

The WATCHMAN device is the most clinically studied product of its kind currently available. In the multi-center, randomized PROTECT AF clinical trial, it proved to be non-inferior to warfarin and demonstrated a 38 percent relative risk reduction for a combined measure of stroke, cardiovascular death and systemic embolism compared to long-term warfarin therapy in 800 patients. The study also showed a 29 percent relative risk reduction in all stroke and a 90 percent relative risk reduction in hemorrhagic stroke compared to warfarin. Nearly 1,800 patients have now been recruited in WATCHMAN clinical trials with more than 2,700 patient-years of follow-up. The WATCHMAN device is CE Marked and was commercialized outside the United States in 2009.

“The WATCHMAN device has been well received in many CE Mark countries and we look forward to beginning commercial launch in select Latin American markets this quarter,” said Hank Kucheman, Chief Executive Officer for Boston Scientific. “We are pleased to bring this technology to more customers and their patients worldwide.”

Boston Scientific is currently enrolling U.S. patients in the PREVAIL study, a confirmatory study designed to gain Food and Drug Administration approval. Enrollment is expected to be completed in the first quarter of 2012. In the U.S., the WATCHMAN device is an investigational device, limited by applicable law to investigational use and not available for sale. The device was developed by Atritech, which Boston Scientific acquired in March 2011.

Abiomed Announces Symphony, an Implantable Synchronized Heart Pump Designed for Chronic Heart Failure Patients, at AHA 2011

Abiomed Inc., a leading provider of breakthrough heart support technologies, announced Symphony, a new synchronized minimally invasive implantable cardiac assist device, designed to treat chronic patients with moderate heart failure by improving patient hemodynamics, and potentially improving quality of life. The device is designed with the primary goal of stabilizing the progression of heart failure and/or recovering/remodeling the heart. Prior to this, no current implantable cardiac assist device had been designed for heart recovery or remodeling.

The small, minimally invasive device is remotely implanted and requires a simple “pacemaker” pocket insertion, avoiding a sternotomy. It is designed to recover and/or remodel the patient’s heart muscle with the intent to explant the device after extended support at home. Symphony is designed to offer the following potential benefits for heart failure patients:

  • Cost-effective solution to improve patient hemodynamics
  • Alleviate heart failure and angina symptoms
  • Preserve end-organ function

Symphony’s simple design enables physicians to implant the device with a single graft to the subclavian artery remotely from the heart. A small pocket under the skin to hold the device is made using the same incision. The Symphony is synchronized to the heart through subcutaneous electrocardiogram leads and provides an output of 3.0 L/min at 100 beats per minute and is designed to potentially:

  • Reduce the afterload, decreasing the work of the left ventricle
  • Increase the cardiac output and mean arterial pressure
  • Increase the coronary and systemic blood flow

Symphony is designed to be a cost-effective alternative for New York Heart Association (NYHA) Class III patients who are not amenable to revascularization, do not respond to inotropes and/or cardiac resynchronization therapies (CRT), and continue to experience poor quality of life with frequent hospital admissions. Additionally, these patients maintain all future options such as medications, adjunctive therapies (pharma, stem cell) as well as heart transplantation or implantable left ventricular assist devices (LVADs).

Symphony’s simple design will provide a lower price point than conventional implantable LVADs. The minimally invasive implantation should lead to a shorter length of stay before the patient is discharged home.

The product has been under development for several years and has solid patent coverage. The product was unveiled in a presentation made by Robert Dowling, MD, at the American Heart Association (AHA) 2011 Scientific Sessions in Orlando, Florida. The first-in-man procedure is expected early next year outside of the United States.

The company will discuss more details on the Symphony specifications and timeline at the Investor Day on December 9, 2011, in New York.

About Abiomed
Based in Danvers, Massachusetts, Abiomed, Inc. is a leading provider of medical devices that provide circulatory support to acute heart failure patients across the continuum of care in heart recovery. Our products are designed to enable the heart to rest, heal and recover by improving blood flow and/or performing the pumping of the heart.

New Subanalyses of RE-LY® Trial Evaluate PRADAXA in Subsets of Patients with Non-Valvular Atrial Fibrillation 

A new retrospective subanalysis of the RE-LY® trial found Pradaxa® (dabigatran etexilate mesylate) capsules 150mg twice daily reduced the risk of stroke and systemic embolism compared to warfarin in patients with non-valvular atrial fibrillation (NVAF) irrespective of the presence of symptomatic heart failure (sHF), with no significant interaction for major bleeding events.1 The results were presented at the American Heart Association’s Scientific Sessions 2011.

Heart failure is a serious condition that occurs when the heart is unable to pump enough blood to meet the body’s needs.2 Up to 30 percent of heart failure patients have atrial fibrillation (AFib),3 and heart failure can increase the risk of stroke for patients with AFib.4 Heart failure also can increase the risk of bleeding in anticoagulated patients.5

“Since heart failure and AFib frequently coexist, this subanalysis is particularly important to physicians who treat patients with non-valvular atrial fibrillation,” said Paul Reilly, PhD, clinical program director, Boehringer Ingelheim Pharmaceuticals, Inc. “These findings add to the growing body of data about the use of PRADAXA in this patient population.”

The subanalysis assessed the effects of PRADAXA 150mg twice daily compared to warfarin in a prespecified subset of patients with previous sHF (n = 4,904).1 The analysis found that while annual event rates of stroke or systemic embolism were higher overall for patients with sHF at baseline (PRADAXA 150mg: 1.44%; warfarin: 1.92%) than those without sHF (PRADAXA 150mg: 1.00%; warfarin: 1.64%), PRADAXA 150mg twice daily reduced the risk of stroke compared to warfarin for both groups of patients (HR = 0.75 for patients with sHF; HR = 0.61 for patients without sHF; p-value for interaction = 0.39).1

Annual event rates for major bleeding were lower with PRADAXA 150mg twice daily than warfarin in patients with sHF at baseline (PRADAXA 150mg: 3.10%; warfarin: 3.90%) and those without sHF (PRADAXA 150mg: 3.39%; warfarin: 3.45%).1 There was no significant interaction for major bleeding events between the two subgroups of patients (HR = 0.79 for patients with sHF; 0.99 for patients without sHF; p-value for interaction = 0.74).1 Additionally, annual rates of intracranial bleeding were lower with PRADAXA 150mg twice daily than warfarin in patients with sHF at baseline (PRADAXA 150mg: 0.26%; warfarin: 0.65%) and those without sHF (PRADAXA 150mg: 0.34%; warfarin: 0.80%).1 There was no significant interaction for intracranial bleeding events between the two subgroups of patients (HR = 0.39 for patients with sHF; 0.42 for patients without sHF; p-value for interaction = 0.72).1

“It is important that we continue to analyze the data from RE-LY to better understand the use of PRADAXA in different types of non-valvular atrial fibrillation patients,” said John Smith, MD, PhD, senior vice president for clinical development and medical affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “Boehringer Ingelheim is committed to informing physicians about the clinical implications for patients taking PRADAXA through data analyses such as these.”

PRADAXA was approved by the U.S. Food and Drug Administration in October 2010 to reduce the risk of stroke and systemic embolism in patients with NVAF.6 PRADAXA has been shown to reduce both ischemic and hemorrhagic stroke compared to warfarin in patients with NVAF.6 In the first eleven months after approval, more than 420,000 patients in the U.S. were prescribed PRADAXA.7 Dabigatran is recommended in a 2011 update to atrial fibrillation treatment guidelines.

Additional RE-LY Subanalysis Presented at AHA
A second subanalysis assessed the risk of peri-operative bleeding with PRADAXA 150mg twice daily compared to warfarin in patients undergoing surgery (n = 4,615).8 In the analysis, the peri-operative phase was defined as seven days before until 30 days following the procedure.8 The analysis found no significant difference in the risk of bleeding, including major (RR = 1.08; p = 0.64), minor (RR = 1.15; p = 0.25), fatal (RR = 1.01; p = 0.99), bleeding requiring re-operation (RR = 1.39; p = 0.32), and bleeding requiring red blood cell transfusion (RR = 0.85; p = 0.37), between patients receiving PRADAXA 150mg twice daily compared to warfarin.8 The analysis also found that patients in all treatment arms who had emergency surgery were at much higher risk of major bleeding than those undergoing elective surgery (PRADAXA 150mg: 17.4% vs. 3.8%; warfarin: 21.7% vs. 3.3%; p<0.001 for all); however, there was no significant difference between treatment arms for either type of surgery.8 Additionally, in all treatment arms, major bleeding was more common for major compared to minor surgery (PRADAXA 150mg: 6.4% vs. 3.2%; warfarin: 8.0% vs. 1.8%; p<0.01 for all), with no significant difference between treatment arms.8

About RE-LY
RE-LY was a global, Phase III, randomized trial of 18,113 patients6 enrolled in 951 centers in 44 countries,9 investigating whether dabigatran etexilate (two blinded doses) was as effective as well-controlled warfarin – INR 2.0 - 3.0 – (open label) for stroke prevention.6 Patients with non-valvular AFib and at least one other risk factor for stroke (i.e., previous ischemic stroke, transient ischemic attack, or systemic embolism, left ventricular dysfunction, age greater than or equal to 75 years, age greater than or equal to 65 years with either diabetes mellitus, history of coronary artery disease, or hypertension) were enrolled in the study for two years6 with a minimum follow-up period of one year.10

The RE-LY trial utilized the established PROBE (prospective, randomized, open-label, blinded endpoint evaluation) clinical trial protocol,10 which has been used in the previous trials of anticoagulation for stroke prevention in patients with AFib.10 A PROBE design may reflect the differences in the management of warfarin and dabigatran in clinical practice.10

The primary endpoint of the trial was incidence of stroke (including hemorrhagic) and systemic embolism.10 Safety endpoints included bleeding events (major and minor), intracerebral hemorrhage, other intracranial hemorrhage, elevations in liver transaminases, bilirubin and hepatic dysfunction and other adverse events.10

In the RE-LY trial, all clinical outcomes were adjudicated in a blinded manner to assess outcomes for each treatment.10

About Pradaxa® (dabigatran etexilate) Capsules

Indications and Usage
Pradaxa® (dabigatran etexilate mesylate) capsules is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.


PRADAXA is contraindicated in patients with active pathological bleeding and patients with a known serious hypersensitivity reaction (e.g., anaphylactic reaction or anaphylactic shock) to PRADAXA.

Risk of Bleeding
PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Risk factors for bleeding include:

  • Medications that increase the risk of bleeding in general (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs)
  • Labor and delivery

Promptly evaluate any signs or symptoms of blood loss, such as a drop in hemoglobin and/or hematocrit or hypotension. Consider evaluation of renal function. Discontinue PRADAXA in patients with active pathological bleeding.

Temporary Discontinuation of PRADAXA
Discontinuing PRADAXA for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of stroke. Lapses in therapy should be avoided, and if PRADAXA must be temporarily discontinued for any reason, therapy should be restarted as soon as possible.

Effect of P-gp Inducers and Inhibitors on Dabigatran Exposure
The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided. P-gp inhibition and impaired renal function are major independent factors in increased exposure to dabigatran. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to increase exposure of dabigatran compared to either factor alone.
*    For patients with moderate renal impairment (CrCl 30-50 mL/min), consider reducing the dose of PRADAXA to 75 mg twice daily when dronedarone or systemic ketoconazole is coadministered with PRADAXA.
*    For patients with severe renal impairment (CrCl 15-30 mL/min), concomitant use of PRADAXA and P-gp inhibitors should be avoided.

In the pivotal trial comparing PRADAXA to warfarin, the most frequent adverse reactions leading to discontinuation of PRADAXA were bleeding and gastrointestinal (GI) events. PRADAXA 150 mg resulted in a higher rate of major GI bleeds and any GI bleeds compared to warfarin. In patients greater than or equal to 75 years of age, the risk of major bleeding may be greater with PRADAXA than with warfarin. Patients on PRADAXA 150 mg had an increased incidence of GI adverse reactions. These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and GI ulcer). Drug hypersensitivity reactions were reported in <0.1% of patients receiving PRADAXA.

Other Measures Evaluated
The risk of myocardial infarction was numerically greater in patients who received PRADAXA 150 mg than in those who received warfarin.

  1. Ferreira J, et al. "Dabigatran Compared With Warfarin In Patients With Atrial Fibrillation And Symptomatic Heart Failure: A Subgroup Analysis Of the RE-LY Trial." AHA 2011 abstract.
  2. NHLBI website. "What Is Heart Failure?" Available at: Accessed on Oct. 31, 2011.
  3. Dries DL, et al. Atrial Fibrillation Is Associated With an Increased Risk for Mortality and Heart Failure Progression in Patients With Asymptomatic and Symptomatic Left Ventricular Systolic Dysfunction: A Retrospective Analysis of the SOLVD Trials. J Am Coll Cardiol 1998;32:695-703.  
  4. Fuster V, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation – Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation):  Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114:700-752.
  5. Lip GY, et al. Comparative Validation of a Novel Risk Score for Predicting Bleeding Risk in Anticoagulated Patients with Atrial Fibrillation. J Am Coll Cardiol 2011;57:173-180.
  6. Pradaxa Prescribing Information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; November 2011.
  7. IMS Health, Custom LRx Study for the period Oct-10 to Sept-11, includes Retail and Mail Order channels, excludes Long-Term Care and Hospital Channels.
  8. Healey JS, et al. "The Risk of Peri-Operative Bleeding with Warfarin Compared to Two Doses of Dabigatran: Results from the RE-LY Trial." AHA 2011 abstract.
  9. Connolly SJ, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009;361:1139-1151.
  10. Ezekowitz MD, et al. Rationale and design of RE-LY: Randomized evaluation of long-term anticoagulation therapy, warfarin, compared with dabigatran. Am Heart J 2009;157:805-810.

Stereotaxis Launches Odyssey Cinema Studio as the Industry’s First Clinical Procedure Online Broadcast Platform

Stereotaxis Partners with NACCME’s Cardiovascular Learning Network® to Deliver Live Broadcasts for Online Medical Education

Stereotaxis, Inc. announced the launch of Odyssey Cinema Studio, an industry-first clinical procedure online broadcast platform providing a turn-key solution for hospitals to facilitate high definition remote physician collaboration and global medical education.

The Odyssey Cinema Studio solution is the latest addition to the company’s Odyssey family of products, which provides hospitals with the necessary information management platform to manage, control, share and broadcast clinical data. With Odyssey Cinema Studio, hospitals can now share a comprehensive view of live and recorded clinical procedures from anywhere around the world for the delivery of global medical education. Procedures that are broadcasted on the Odyssey Network feature a consolidated view of the systems within the interventional lab in high definition, preserving the fine details of diagnostic and imaging data. Physicians will be able to conduct an Internet-based broadcast and presentation with minimal preparation time to a virtually unlimited number of participants.

“Odyssey is an optimal solution for capturing and delivering synchronized procedure information throughout hospitals. We acquired Odyssey after careful review to select what we felt is the most advanced technology to support the initiatives of our world-class practice,” said Dr. Yaariv Khaykin, MD, FRCPC, FACC, FHRS, Director, Newmarket Electrophysiology Research Group, Southlake Regional Health Centre. “We are excited to begin using the Cinema Studio upgrade since we anticipate it will take the platform to a whole new level by allowing our institution to broadcast and collaborate in an unprecedented way.”

The Odyssey Cinema Studio can be purchased by hospitals as a premium version of the Odyssey Cinema offering or as an upgrade to existing Odyssey Cinema installations. Stereotaxis has completed initial Odyssey Cinema Studio upgrades at two world-class hospitals including the Texas Cardiac Arrhythmia Institute at St. David’s Medical Center in Austin, Texas and Southlake Regional Healthcare Centre in Ontario, Canada, and expects to fulfill the first new customer delivery in the fourth quarter of 2011.

Stereotaxis also announced an agreement with the North American Center for Continuing Medical Education, LLC (NACCME) to accelerate the advancement of cardiovascular care worldwide as their exclusive live broadcast platform for delivering medical education via the Odyssey Cinema Studio. NACCME, an accredited medical education provider, is introducing the Cardiovascular Learning Network® (CVLN) to enhance its ability to bring innovative, high-quality education to its network of more than 26,000 cardiovascular medical professionals. Stereotaxis and NACCME/CVLN will jointly broadcast educationally relevant cases to the worldwide cardiovascular community, supporting collaboration and best practice sharing to improve patient care. These cases will also include the ability for participants to interact with world-renowned professionals through online question and answer capabilities.

“We expect that Internet-enabled procedure broadcasts will transform medical education as participants can remotely view procedures in high definition, often related to the latest medical treatment techniques used by world-class physicians,” said Michael P. Kaminski, Stereotaxis President and CEO. “We are very excited that Odyssey Cinema Studio has been chosen as the exclusive live online broadcasting platform by NACCME and its new Cardiovascular Learning Network® to jointly provide far-reaching medical education from Odyssey-equipped labs around the world.”

Update on AtriCure’s DEEP AF Feasibility Trial

AtriCure, Inc., a medical device company and a leader in cardiac surgical ablation systems and systems for the exclusion of the left atrial appendage, announced that it has closed enrollment in its DEEP AF feasibility trial. DEEP AF was designed to evaluate the safety and efficacy of combining AtriCure’s minimally invasive products with catheter technologies to treat patients with persistent and longstanding persistent atrial fibrillation (AF). The procedure, also known as hybrid ablation, combines epicardial and endocardial ablation and mapping as part of a single session procedure. To date, 24 of 30 patients have been enrolled in the trial.

At a recent meeting, study investigators reviewed the clinical results and discussed the logistics of performing the hybrid ablation procedure in a single session. As a result of the discussion, AtriCure determined that a staged approach, where the minimally invasive surgical ablation procedure is performed and the catheter optimization is scheduled separately, may be more applicable to a larger number of investigators as AtriCure plans for a pivotal trial and commercialization. Consequently, AtriCure decided to close enrollment in the DEEP AF trial.

“We reached the decision to close enrollment in this feasibility study because we accomplished our objective of gaining a better understanding of the procedure prior to proceeding to a pivotal trial,” said David J. Drachman, President and Chief Executive Officer. “This feasibility study has demonstrated that the single session procedure is highly encouraging. However, it can present scheduling and logistical challenges as we look to widespread adoption. As a result, we are in the process of reviewing staged procedure alternatives and we plan to discuss these options with the FDA in the near term.”

Seven patients in the DEEP AF trial have six-month follow-up data, which was documented through 14-day continuous Holter monitoring. None of the patients experienced episodes of AF or atrial flutter. One patient experienced episodes of atrial tachycardia. Antiarrhythmic drugs were discontinued prior to rhythm assessment in all 7 patients. Of the 24 patients treated, 7 experienced primary adverse events that were reported and independently adjudicated. None of the adverse events were attributed to the investigational device. At the suggestion of the study investigators, an independent physician adjudicator graded the adverse events as mild, moderate or severe. All of the events were categorized as mild or moderate, except for one event that was classified as severe. The severe event was a stroke that occurred 27 days post procedure and resulted in death on day 30. The cause of the stroke could not be determined; therefore, it was attributed to the procedure.

Dr. Steven J. Hoff, Assistant Professor, Department of Cardiac Surgery, Vanderbilt University Medical Center, commented, “We are impressed with the results from this hybrid ablation procedure for the treatment of AF patients. In the DEEP AF trial, the acute procedure success and six-month efficacy data, while limited, was very encouraging. The acute results demonstrated the confirmation of effective block in all attempted lesions. From our growing experience, we believe that this hybrid ablation procedure is highly impressive given this difficult to treat group of persistent and longstanding persistent AF patients.”

Dr. Paul J. Wang, a leading electrophysiologist and Professor of Medicine, Director of Stanford Arrhythmia Service, commented, “I am very encouraged by the ability of the hybrid surgical and catheter ablation approach to restore sinus rhythm in patients with persistent and longstanding persistent AF, even in the presence of significantly enlarged atria. We look forward to continuing the investigation of this promising procedure when the study is revised and restarted in the future.”

Patients With Severe Sepsis and New-Onset Atrial Fibrillation at Increased Risk of In-Hospital Stroke, Death

Patients hospitalized with severe sepsis who experience new-onset atrial fibrillation have an associated increased risk of in-hospital stroke and death, according to a study appearing in JAMA. The study was released early online to coincide with its presentation at the American Heart Association Scientific Sessions.

Atrial fibrillation (AF) is one of the most common arrhythmias among critically ill patients. “Previous studies have demonstrated that 6 percent to 20 percent of patients with severe sepsis develop new-onset AF, suggesting that severe sepsis may be a predisposing factor for new-onset AF,” according to background information in the article. “Chronic AF is a known risk factor for stroke and death, but the clinical significance of new-onset AF in the setting of severe sepsis is uncertain.”

To examine the association of new-onset AF during severe sepsis with adverse outcomes of in-hospital mortality and ischemic stroke, Allan J. Walkey, MD, MSc, of the Boston University School of Medicine, and colleagues conducted a study that included administrative claims data from the California State Inpatient Database from nonfederal acute care hospitals for January 1 through December 31, 2007. Data were available for 3,144,787 hospitalized adults. The researchers identified 49,082 cases of severe sepsis that met qualifying criteria for the study. New-onset AF was defined as AF that occurred during the hospital stay, after excluding AF cases present at admission.

New-onset AF occurred during 20,608 hospitalizations (0.65 percent; including sepsis and nonsepsis) and during 2,896 hospitalizations (5.9 percent) of patients with severe sepsis, with analysis indicating that 14 percent of all hospital-associated new-onset AF occurred in the context of severe sepsis. Compared with hospitalized patients without severe sepsis, patients with severe sepsis had nearly 7 times the odds of having new-onset AF. Factors associated with increased risk of new-onset AF during severe sepsis included demographics (increasing age, male sex, and white race), comorbidities (history of heart failure, obesity, malignancy, and stroke), and various acute factors (such as increasing number of organ failures, respiratory failure and renal failure).

Among individuals with severe sepsis, new-onset AF was associated with increased adjusted risks of in-hospital ischemic stroke. In contrast, patients with severe sepsis and preexisting AF did not have an increased risk of in-hospital ischemic stroke compared with those with severe sepsis and no AF. In patients with severe sepsis, in-hospital ischemic stroke occurred in 75 of 2,896 individuals (2.6 percent) with new-onset AF compared with 57 of 9,986 (0.57 percent) with preexisting AF and 249 of 36,200 (0.69 percent) without AF.

Compared with severe sepsis patients without new-onset AF, patients with new-onset AF had a greater risk of in-hospital mortality (1,629 [56 percent] vs. 18,027 [39 percent] deaths).

The researchers speculate that several potential mechanisms might explain the increased ischemic stroke risk in patients with severe sepsis and new-onset AF. “Severe sepsis alone may be associated with an increased risk of stroke through hemodynamic [blood circulation] collapse, increased systemic inflammation, and coagulopathy [clotting/bleeding disorder]. New-onset AF may simply be a marker for greater severity of illness and, thus, greater stroke risk.”

“Given projected estimates of severe sepsis incidence in 1 million Americans in 2011, it is likely that new-onset AF occurs in more than 60,000 patients with severe sepsis in the United States each year,” the authors write. “Current guidelines do not address AF that occurs in the setting of severe sepsis or acute infection, suggesting that new-onset AF that occurs during severe sepsis is an underrecognized public health problem. If our findings of increased stroke and death in the setting of AF and severe sepsis are replicated in other data sets, then it will be important to examine management strategies that might diminish the risk of adverse outcomes associated with AF during severe sepsis.”

JAMA 2011;306[20]:2248-2255.

Gencaro Demonstrated 74% Risk Reduction for New Onset Atrial Fibrillation in Heart Failure Patients with Genotype Believed to Be Found in Nearly 50% of Population

ARCA biopharma, Inc., a biopharmaceutical company developing genetically-targeted therapies for atrial fibrillation and other cardiovascular diseases, announced results of analyses of atrial fibrillation and pharmacogenetic data from the BEST trial, a previously conducted Phase 3 heart failure trial involving Gencaro in 2,708 advanced heart failure patients. Pursuant to their analysis, researchers concluded that Gencaro substantially decreased the risk of new-onset atrial fibrillation in a large moderate-to-severe heart failure population, with a risk reduction of 41%. Furthermore, the researchers concluded that patients with a specific genotype (homozygous arginine at beta-1 389) had a 74% risk reduction for new-onset atrial fibrillation. Based on a DNA sub-study in the BEST trial, ARCA believes approximately 50% of U.S. population has this specific genotype.

The data were selected for oral presentation at the American Heart Association’s Scientific Sessions 2011 in Orlando, Florida. Dr. Ryan Aleong, Assistant Professor of Medicine, Cardiology, Director of Implanted Cardiac Device Clinic, University of Colorado Hospital, and Interim Director of Arrhythmia Services at Denver Health Medical Center, presented the abstract “Prevention of Atrial Fibrillation by Bucindolol is Completely Dependent on the Beta-1 389 Arg/Gly Adrenergic Receptor Polymorphism.”

Data presented in the abstract included:
Beta blockers have modest efficacy for the prevention of atrial fibrillation in chronic heart failure/reduced ejection fraction (HFREF) populations, with risk reductions on the order of 20–40%. The researchers assessed the ability of the beta-blocker/sympatholytic agent Gencaro to prevent atrial fibrillation in the BEST trial, identifying new-onset atrial fibrillation from adverse event/serious adverse event (AE/SAE) case report forms as well as routinely measured electrocardiograms (ECGs) in patients not in atrial fibrillation on study entry, and constructing Kaplan-Meier curves using Cox regression. In the entire 2,708 patient cohort there were 115/1190 (9.7%) new-onset atrial fibrillation episodes in baseline sinus rhythm patients in the placebo group, and 75/1202 (6.2%) in the Gencaro group. The time to event hazard ratio (95% CIs) was 0.59 (0.44, 0.79), p = 0.0004. In the 1,040-patient DNA substudy based on 80 total events, the hazard ratio was 0.57 (0.36, 0.90), p = 0.014) and the therapeutic effect was completely dependent on the beta-1 389 Arginine/Glycine polymorphism.

Conclusions from the analysis included: 1) Gencaro produced substantial prevention of atrial fibrillation in the entire BEST population, with a risk reduction of 41%; 2) the risk reduction for new-onset atrial fibrillation was pharmacogenetically determined, with patients who were homozygous arginine at beta-1 389 having a 74% risk reduction and patients having any glycine at this position having no effect. This effect differentiation is greater than for heart failure mortality or hospitalization endpoints, where the homozygous arginine at beta-1 389 genotype is associated with risk reductions of 34–48% vs. 8–22% in the glycine at any position genotypes.