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Advanced Cardiac Therapeutics Initiates First-In-Man CE Mark Clinical Trial to Study Innovative Catheter System for the Treatment of Atrial Arrhythmias

Advanced Cardiac Therapeutics, Inc., a developer of innovative temperature-sensing cardiac ablation systems, announced that the first patients have been enrolled in a first-in-man CE Mark clinical trial of the safety and performance of the company’s TEMPASURE™ cardiac ablation catheter. The TEMPASURE system is the world’s first RF cardiac ablation catheter to offer both saline irrigation and temperature-sensing technology. The TEMPASURE system is designed to result in better outcomes for patients by reducing overall procedure time and increasing therapeutic effectiveness, while avoiding rare but serious adverse events. The system’s novel passive sensing microwave radiometry technology allows the electrophysiologist to measure the temperature of cardiac tissue at three millimeters depth during the ablation procedure, providing real-time information that enables proper energy delivery and lesion control. “ACT’s novel catheter system directly measures lesion creation through temperature, addressing a longstanding problem for physicians performing irrigated cardiac ablation,” said Karl-Heinz Kuck, MD, head of the Department of Cardiology, St. Georg Hospital, Germany, who is co-principal investigator of the trial. “I’m very excited about the promise of this new technology to increase the safety and success of cardiac ablation procedures.” “I found the ACT system straightforward to use, requiring no different handling or training,” said Yves Vandekerckhove, MD, chairman of the Department of Cardiology at Sint Jan Hospital in Bruges, Belgium, who performed the first-ever procedure with the system. “Even in the first few patients, we were able to see clinical therapeutic outcomes that closely matched the temperature measurements. The patients I have treated are doing very well.” “Many years ago, the addition of a thermocouple enabled precise temperature control and temperature mode energy delivery to standard RF catheters. In a similar way, this microwave radiometry technology promises to significantly advance the way we perform irrigated RF ablations for patients with cardiac arrhythmias,” said Pedro Brugada, MD, professor of Cardiology, chairman and scientific director, Cardiovascular Division, UZ Brussel, Brussels, Belgium, the study’s co-principal investigator. The prospective, multi-center, single arm study will enroll up to 30 patients with atrial flutter in Europe and New Zealand. Patients enrolled in the trial will be studied during ablation, with follow up at seven and 30 days. Operators are blinded to the microwave radiometer signal in the trial procedures, using ACT’s catheter in exactly the same way as for current irrigated procedures. “The initiation of our first-in-man study marks a major milestone for ACT,” said Peter van der Sluis, the company’s CEO. “We are very excited to soon launch the TEMPASURE temperature-sensing ablation catheter.” Kenneth Carr, Dr. Eng. who pioneered microwave radiometry technology, commented, “It is incredibly exciting to see my life’s work proceed to clinical use and directly benefit patients with cardiac arrhythmias.”

BIOTRONIK Introduces Industry’s Smallest Implantable Cardiac Device Programmer

BIOTRONIK SE & Co. KG announced the European market launch of their new Renamic implantable cardiac device programmer. Renamic is the latest addition to BIOTRONIK’s new portfolio of external devices launched within only a few months. The benefits of Renamic have been confirmed in more than 1,000 follow-up user tests. Its new user interface has been optimized with improved use of spacing and an intuitive color coding. The touchscreen can either be used with the stylet — or with any other tool, from fingers to ordinary pens. Besides being the smallest programming device in its class, Renamic features special compartments for accessories such as the power cord, so they can be stored within the device during transportation. To ensure maximum compatibility with other systems and technologies, Renamic offers multiple options for data transmission, including Bluetooth^®, Global System for Mobile Communications (GSM) and wireless LAN (Wi-Fi^®). Furthermore, Renamic is already prepared to accommodate BIOTRONIK SafeSync, which allows for wireless interrogation of the implanted cardiac devices. “In combination with Reocor, our new external pacemaker, and Reliaty, our new pacing system analyzer, Renamic completes a rapid succession of brand new external device releases,” stated Marlou Janssen, Vice President, Global Marketing and Sales, Cardiac Rhythm Management, BIOTRONIK. “Renamic once again exemplifies BIOTRONIK’s focus on developing high quality solutions for advanced patient management.” The programmer is used for initial programming, reprogramming and testing of implantable pacemakers, implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy (CRT) devices after implantation. By conducting all measurements and adjustments, Renamic helps clinicians to optimize individual patient therapy. “The new Renamic programmer is the result of intensive collaboration between engineers and clinicians and is optimally suited for the requirements in daily clinic routines,” says Dr. Heiner Vontobel, Head Cardiologist at Zuercher Oberland Healthcare, Switzerland. “The device’s easy handling and simple programming help to increase my clinic efficiency. Plus, the device’s robust design makes it very reliable.”

Medtronic CareLink^® Network Remote Monitoring Helps Improve Patient Care and Reduce Healthcare Costs

Medtronic, Inc. announced results from a clinical trial that showed remote monitoring of implantable cardiac device patients with the company’s CareLink® Network with automatic Medtronic CareAlert^® Notifications reduces healthcare utilization costs compared to standard in-office follow-up. Key findings of the CONNECT (Clinical Evaluation of Remote Notification to Reduce Time to Clinical Decision) trial show that remote monitoring reduces the time from a clinically-actionable event to a clinical decision by 79 percent (p1 Patients in the trial who had a successful AT/AF burden alert leading to a remote transmission saw a median of 3 days from the onset of their arrhythmia to clinical action, compared to 24 days in the group relying only on routine in-office visits. According to the study authors, this may have resulted from the high percentage of asymptomatic atrial fibrillation in this population. Without the development of symptoms, AF would only be detected at the time of a routine visit, or a hospital admission that may have been triggered by an embolic event or worsening of heart failure due to the atrial fibrillation. “Our CareLink Network is a vital, clinically validated patient management tool that is associated with numerous benefits, as demonstrated in the CONNECT trial,” said Pat Mackin, president of the Cardiac Rhythm Disease Management business and senior vice president at Medtronic. The CareLink Network, which has more than 4,500 clinics and nearly 600,000 patients enrolled in 31 countries,² was recently awarded ISO 27001 certification, a stringent worldwide information security standard.

About the CONNECT trial

The multi-center, prospective CONNECT trial randomized 1,997 patients implanted with an ICD with or without CRT capabilities, from 136 sites in the United States to remote monitoring versus standard in-office care. The study evaluated the time from clinical event to clinical decision in response to the event, as well as the associated impact on health care utilization, such as hospitalizations and visits to the emergency department. All patients were followed for 15 months post-implant. The 1,014 patients monitored remotely were given Medtronic’s wireless remote management system, consisting of the Medtronic CareLink Network, CareLink Patient Home Monitor, Concerto® CRT-D and/or Virtuoso® ICD with Conexus® Wireless Telemetry, and CareAlert^® Monitoring, for transmitting patient device diagnostic data accessible in the physician’s office. These devices used wireless telemetry, allowing the automatic transmission of diagnostics to the physician. The 983 patients receiving in-office care were followed at a fixed standard-of-care schedule, without remote monitoring.

About the Medtronic CareLink Network

The Medtronic CareLink Network offers customizable and color-coded alert notifications for devices with Conexus Wireless Telemetry. Through this network, patient device diagnostic data are transmitted from their implantable device using a portable monitor that is connected to a standard telephone line or the Medtronic M-Link^® Cellular Accessory. Within minutes, the patient’s physician and nurses can view the data on a secure Internet web site. Available information includes arrhythmia episode reports and stored electrograms along with device integrity information, which is comparable to the information provided during an in-clinic device follow-up visit, and provides the physician with a view of how the device and patient’s heart are operating. ¹Capucci, 2005; Ousdigian, 2005; Wang, 2003; Bala, 2006. ²CareLink Metrics Database (February 2011).

deCODE Discovers Genetic Risk Factor for Sick Sinus Syndrome

Scientists at deCODE genetics and academic colleagues from Iceland, The Netherlands, Denmark, USA and Illumina, Inc., report the discovery of single-letter variants (SNPs) in the sequence of the human genome associated with high risk of sick sinus syndrome (SSS). The study is published in the online edition of Nature Genetics. The study reports a genetic variant in the gene MYH6 that is associated with high risk of sick sinus syndrome (SSS) in Icelanders. The lifetime risk of being diagnosed with SSS is about 6% for individuals without this genetic variant but is increased by 12.5 times, to approximately 50%, for those that carry the variant. SSS is a heart rhythm disorder that is characterized by an inappropriately slow heart rate. It is commonly seen in the elderly and many with SSS eventually need a permanent pacemaker. With the aim of searching for sequence variants that predispose to SSS, a genome-wide association study was performed including 792 Icelanders with SSS and 37,592 Icelandic controls. The study utilized SNP data from several sources including Illumina SNP chip genotyping as well as whole-genome sequencing of 7 Icelanders with SSS and 80 Icelanders not diagnosed with SSS. The whole-genome sequencing data yielded a strong association between SSS and a rare missense mutation in MYH6 that could not be accounted for by any other sequence variation. MYH6 encodes one form of myosin, a major component of the contractile system of the heart, and was recently associated with the function of the conduction system of the heart by studies from deCODE and others. This is the first time that MYH6 is implicated in the development of heart rhythm disorders. “This work constitutes our first entry into the study of rare variants in common diseases that confer large risk of disease. It is clear that the risk of common diseases in our society is accounted for by both common and rare variants in the sequence of the genome. We here at deCODE and scientists all over the world have over the past few years discovered large numbers of common variants that confer risk of common diseases. Now we are entering into the era of rare variants that are providing us with clear insights into the pathogenesis of diseases and possibilities of putting together very effective diagnostics,” said Kari Stefansson, deCODE's CEO and senior author of the study. The paper, “A rare variant in MYH6 is associated with high risk of sick sinus syndrome,” is published online in Nature Genetics at https://www.nature.com/ng and will appear in an upcoming print edition of the journal. Sick sinus syndrome, or sinus node dysfunction, is a common clinical disorder that is characterized by pathological slow heart rate, sinus arrest and/or attenuated heart rate response to exercise. The syndrome comprises a wide range of electrophysiological abnormalities, including failure of the sinus node and atrial impulse formation or propagation, as well as susceptibility to atrial tachyarrhythmias, particularly atrial fibrillation. Although encountered at any age, SSS is primarily a disease of the elderly and is often secondary to other cardiac disorders when diagnosed in younger individuals. Symptoms are often intermittent and/or nonspecific and include dizziness, syncope and heart failure. The only effective treatment for symptomatic and irreversible sinus node dysfunction is permanent cardiac pacing, and SSS remains the most common indication for permanent pacemaker implantation.

In Pilot Study, Screening Detects Potentially Serious Heart Conditions in Healthy Children: The Children’s Hospital of Philadelphia Study Shows Feasibility of Screening for Risk of Sudden Cardiac Arrest

A pilot study in healthy children and adolescents shows that it is feasible to screen for undiagnosed heart conditions that increase the risk of sudden cardiac arrest (SCA). Adding a 10-minute electrocardiogram (ECG) to a history and physical examination identified unsuspected cases of potentially serious heart conditions. Although more research is needed, the preliminary results suggest that a relatively low-cost screening might help identify children who are at risk for sudden cardiac arrest, possibly preventing childhood death. “In the United States, the current American Heart Association guidelines recommend screening only competitive athletes, not all children, using history and physical examination alone,” said the study leader, Victoria L. Vetter, MD, MPH, a pediatric cardiologist at The Children's Hospital of Philadelphia. She noted that in Italy and Japan, which have compulsory screening of all athletes or schoolchildren, researchers have found that adding an ECG to the history and physical increases the likelihood of detecting children at risk for SCA. “Our pilot study evaluated the feasibility of adding an ECG to cardiac screening of healthy school-aged children,” Vetter added. The Children's Hospital research team published their study on March 15 in the American Heart Journal.¹ In children, sudden cardiac arrest is caused by structural or electrical abnormalities in the heart that frequently cause no symptoms and may go undiagnosed. It results in an estimated 100 to 1,000 or more annual deaths in childhood in the US. The current study evaluated 400 healthy subjects, 5 to 19 years old, recruited from Children’s Hospital’s Care Network. The researchers screened the subjects using a medical family history questionnaire, a physical examination, an ECG and an echocardiogram. The study team identified previously undiagnosed cardiac abnormalities in 23 subjects, and hypertension in an additional 20. Ten of the 400 subjects (about 2.5 percent) had potentially serious cardiac conditions. Of those 10 subjects, only one had experienced symptoms, and those had previously been dismissed. None of the 10 subjects had a family history of SCA. “In our study, using ECG outperformed the history and physical examination and found previously unidentified potentially serious abnormalities that would not have been identified by history and physical examination alone,” the study authors wrote. The authors added that the children in the screening were not all high school athletes, and most would not have undergone athletic cardiac screening. Regular physical examinations by primary care physicians had not detected the cardiac conditions found in the current study. “Performing the ECG and its interpretation added less than 10 minutes to each subject's total evaluation,” said Vetter, added that the ECG machines are portable and relatively inexpensive. “Our pilot study showed that adding ECG to the currently recommended guideline of history and physical examination is feasible for screening children and adolescents, and offers the potential to identify serious cardiovascular abnormalities,” said Vetter. “However, our study was not designed to be generalizable to a larger population of children at risk for SCA. Larger, more representative studies must be done, as well as cost-effectiveness research.” She added that larger pediatric studies may establish better standards for ECG measurements, and determine how broad ECG screening of school-aged children could best be implemented. ¹Vetter, et al. A pilot study of the feasibility of heart screening for sudden cardiac arrest in healthy children. Am Heart J. Published online [March 15, 2011]; doi: 10.1016/j.ahj.2011.01.022

Pradaxa Gains Preferred Formulary Status with Key Pharmacy Benefit Managers

Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI), announced that Pradaxa^® (dabigatran etexilate mesylate) capsules has received preferred Tier 2 formulary status with CVS Caremark (Commercial Preferred Drug List) and Medco (Commercial Preferred and Part D Drug Lists), two of the largest pharmacy benefit managers covering more than 100 million Americans.¹ The U.S. Food and Drug Administration (FDA) approved PRADAXA in October 2010 to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF).² Five months after FDA approval, PRADAXA is now available at the lowest branded co-pay level on formularies that insure about 35 percent of NVAF patients.¹ For those patients who may not otherwise be able to afford treatment, BIPI offers patient assistance programs to help provide coverage for the costs of their medications. In the pivotal RE-LY trial, PRADAXA 150 mg capsules taken twice daily reduced the incidence of stroke and systemic embolism by 35 percent beyond the reduction achieved with warfarin,2 which was dosed to a target international normalized ratio (INR) of 2.0 to 3.0.² The effects of PRADAXA compared to warfarin were more apparent in patients with lower levels of INR control.² “These formulary additions will offer non-valvular atrial fibrillation patients increased access to PRADAXA, including its demonstrated ability to significantly reduce the risk of stroke over warfarin in this patient population,” said Wa'el Hashad, vice president, cardiovascular and metabolic disorders marketing, Boehringer Ingelheim Pharmaceuticals, Inc. “We look forward to a long relationship with CVS Caremark and Medco, and are committed to working with other pharmacy benefit managers as well as offering our own programs to help make PRADAXA available to patients with non-valvular atrial fibrillation.” PRADAXA is the only FDA-approved treatment that has demonstrated significant reductions in the risk of stroke compared to warfarin in patients with NVAF2 and is the first oral anticoagulant to be approved in the U.S. in more than 50 years in this patient population. About Atrial Fibrillation and Stroke Atrial fibrillation, characterized by an irregular heartbeat,³ can cause blood clots to form in the heart that can travel to the brain and cause a stroke.³ An estimated 2.3 million Americans are living with atrial fibrillation,⁴ and the prevalence is expected to increase to 5.6 million by 2050.⁴ Non-valvular atrial fibrillation, which accounts for up to 95 percent of diagnosed cases of atrial fibrillation,⁴ refers to cases of atrial fibrillation without rheumatic mitral valve disease, prosthetic heart valve or valve repair, according to the 2006 ACC/AHA/ESC guidelines.⁵ Atrial fibrillation increases the risk of stroke nearly five times⁵ and is associated with up to 15 percent of all strokes in the U.S.⁵ Atrial fibrillation imposes a substantial economic burden to the healthcare system,⁶ specifically the high costs associated with stroke.⁷About the Storage and Handling of PRADAXA PRADAXA must be stored in its original packaging² and patients should not transfer the capsules to pill boxes or pill organizers.¹ Once the bottle is opened, the product must be used within 30 days.² Patients must close the bottle tightly immediately after removing one capsule² and must not alter the child-proof cap.¹ It is recommended that patients date the bottle to expire 30 days after first opening. When more than one bottle is dispensed, patients should only open one bottle at a time.¹ When packaged in a blister package, each capsule should only be removed at time of use.² After 30 days, patients should safely throw away any unused PRADAXA capsules.²About Pradaxa^® (dabigatran etexilate) Capsules Indications and Usage PRADAXA is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. IMPORTANT SAFETY INFORMATION ABOUT PRADAXA CONTRAINDICATIONS 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. WARNINGS AND PRECAUTIONS 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., antiplatelet 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. 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 PRADAXA Exposure The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces dabigatran exposure and should generally be avoided. P-gp inhibitors ketoconazole, verapamil, amiodarone, quinidine, and clarithromycin, do not require dose adjustments. These results should not be extrapolated to other P-gp inhibitors. ADVERSE REACTIONS 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 Other Measures Evaluated The risk of myocardial infarction was numerically greater in patients who received PRADAXA 150 mg than in those who received warfarin. For full PRADAXA prescribing information and medication guide, please visit www.pradaxa.com or contact Boehringer Ingelheim's Drug Information Unit at 1-800-542-6257. ¹Data on file. Boehringer Ingelheim Pharmaceuticals, Inc. ²Pradaxa Prescribing Information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2010. ³NHLBI website. “What is AFib?” Available at: https://www.nhlbi. nih.gov/health/dci/Diseases/af/af_what.html. Accessed on: August 2, 2010. ⁴Go AS, et al. Prevalence of Diagnosed Atrial Fibrillation in Adults: National Implications for Rhythm Management and Stroke Prevention: the ATRIA Study. JAMA 2002;285:2370-2375. ⁵Fuster 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 2011 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. ⁶Coyne KS, et al. Assessing the Direct Costs of Treating Nonvalvular Atrial Fibrillation in the United States. Value in Health 2006;9:348-356. ⁷Harley C, et al. Direct Costs And Health Care Utilization Associated With Stroke in the Presence of Atrial Fibrillation in the United States. ASAIS Conference, Feb. 2009.