Remote Active Monitoring in Patients With Heart Failure (RAPID-RF): Design and Rationale

Transcription

1 Journal of Cardiac Failure Vol. 13 No Clinical Trials Methods and Design Remote Active Monitoring in Patients With Heart Failure (RAPID-RF): Design and Rationale LESLIE A. SAXN, MD, 1 JHN P. BEHMER, MD, 2 STACEY NEUMAN, PhD, 3 AND CHRISTPHER M. MULLIN, MS 4 Los Angeles, California; Hershey, Pennsylvania; St. Paul, Minnesota; Brooklyn Park, Minnesota ABSTRACT Background: Heart failure (HF) ambulatory disease management programs appear to offer the greatest benefit to HF patients at highest risk, defined as having New York Heart Association (NYHA) functional Class III or IV symptoms. The Latitude Patient Management System is the first HF management tool to use wireless telemetry present in a cardiac resynchronization therapy defibrillator (CRT-D) device that is linked to remotely collect blood pressure and weight measures, permitting a single transmission reporting device data. Potential advantages of this system include ease of data transmissions, correlation among measures of HF status, arrhythmic events, and device performance. However, the use and ultimate utility of these combined features for patient management are untested. Methods and Results: The Remote Active Monitoring in Patients with Heart Failure (RAPID-RF) study is a multicenter registry that will enroll up to 1000 patients on the Latitude Patient Management System from approximately 100 centers. The primary objective is to examine physician responses to Latitude Active Monitoring data alerts by assessing alert-related medical interventions. Minimum follow-up will be 3 months after implant with a maximum follow-up time of 24 months after implant. Conclusions: The RAPID-RF study will provide important preliminary data on how remotely collected HF and arrhythmic surveillance data alter the management of HF patients with CRT-D devices. (J Cardiac Fail 2007;13:241e246) Key Words: Remote monitoring, heart failure, cardioverter resynchronization therapy, defibrillator. Heart failure (HF) currently affects an estimated 5 million Americans and is 1 of the leading causes for hospitalization in the United States. 1,2 Aging of the US population will likely increase the incidence of HF, but more important, is its prevalence, which is expected to reach an excess of 10 million Americans by the year e5 As more Americans are diagnosed with HF, the demand for specially From the 1 University of Southern California, Los Angeles, California; 2 Hershey Medical Center, Hershey, Pennsylvania; 3 Boston Scientific Corporation, St. Paul, Minnesota; and 4 The Integra Group, Brooklyn Park, Minnesota. Manuscript received ctober 19, 2006; revised manuscript received December 11, 2006; revised manuscript accepted December 19, All decisions regarding this manuscript were made by a guest editor. Reprint requests: Leslie A. Saxon, MD, 1500 San Pablo Street, Second Floor, Los Angeles, CA Sponsored in full by Boston Scientific Corporation. This trial is registered on (trial identifier: NCT ). Leslie A. Saxon is a paid consultant to Boston Scientific Corporation and Medtronic. John P. Boehmer is a paid consultant to Boston Scientific Corporation. Christopher M. Mullin is a paid consultant to Boston Scientific Corporation /$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi: /j.cardfail trained health care individuals will undoubtedly increase. 6 In addition, the recent expansion of primary prevention indications may increase the number of HF patients receiving cardiac resynchronization therapy defibrillator (CRT-D) devices for the treatment of HF. 7,8 Currently indicated populations for CRT-D therapy include those patients having advanced functional class HF on appropriate background medical therapies, QRS duration 120 ms, and left ventricular ejection fraction!35%. It is estimated that CRT-D devices compose onethird of all implantable cardioverter defibrillators in the United States. 9 Disease management programs including remote patient monitoring provide an alternative to frequent clinic visits and more convenience to HF patients with CRT-D devices and to their physicians. 10e12 Several recent studies have also shown improved outcomes associated with home disease management strategies. 13e15 However, these studies were predominantly nurse-driven, labor-intensive, and reliant on individual patient compliance. 5,10,11,13,15 The Weight Monitoring in Heart Failure (WHARF) trial observed a significant reduction in mortality (56.2%), but no differences 241

2 242 Journal of Cardiac Failure Vol. 13 No. 4 May 2007 in hospital readmission rates for patients randomized to an intervention group monitored with a nurse-administered home monitoring system versus a standard-of-care follow-up protocol. 16 The Short- and Long-Term Benefits of Heart Failure Disease Management Within a Diverse Provider Network (SPAN-CHF) trial observed significantly fewer hospitalizations and a reduction in hospital length of stay related to HF compared to a standard-of-care group. 10 Similarly, results from the Trans-European Network-Home- Care Management System (TEN-HMS) study showed a significant reduction in mortality and mean duration of hospital admissions for patients randomized to a nurse telephone support group with home telemonitoring equipment. 6 The ability to remotely monitor device function holds promise, and preliminary data indicate high patient and physician satisfaction. 15 Technology-based remote monitoring may allow for the early diagnosis and treatment of arrhythmias as well as monitor appropriate device function. 6,15 Latitude Patient Management is a system that incorporates wireless radiofrequency (RF) telemetry as a mode for remote patient monitoring, including weight and blood pressure measures, in addition to device information. Examination of this method of HF disease management may present advantages over other more fragmented remote technology by allowing for the more timely transfer of comprehensive implanted device and physiologic (weight, blood pressure, and symptom-related) data remotely and automatically. In addition, remote monitoring of these data made available to physicians via the internet may, in turn, may help them develop informed diagnoses quickly if a device or physiologic issue arises. The Remote Active Monitoring in Patients with Heart Failure (RAPID-RF) study will examine and assess type and frequency of prespecified alert notifications, as well as alert-related medical interventions. These data will then be available to plan and power a randomized clinical trial to assess the efficacy of this intervention. Study Design Methods The RAPID-RF study is a multicenter prospective registry that examines the use of active monitoring in HF patients with a recently implanted CRT-D device. Changes in New York Heart Association (NYHA) functional class, quality of life as assessed using the Global Assessment Tool, 17 Minnesota Living with Heart Failure Questionnaire, 18 hospitalizations, mortality, and device data will be prospectively evaluated. After implant, remote device and patient data will be collected at daily and weekly intervals. Inclinic visit data will be collected according to implantable cardioverter defibrillator implant guidelines at implant, 3- and 6-month visits, and thereafter at designated post 6-month follow-ups, until study closure. 13 Any additional clinic visits not triggered by a device alert resulting from a change in clinical status or requiring a cardiovascular medication change will be captured on a case report form at the next scheduled clinic visit. The entire data collection schedule is listed in Table 1. In addition to being implanted with an RF-enabled CRT-D device, each study patient will receive a Latitude communicator and home monitoring equipment including a weight scale and blood pressure monitor (Fig. 1). The communicator transmits information from the implanted CRT-D device, weight scale, blood pressure monitor, and the patient s answers to weekly symptom self-report questions to a secure server through an analog telephone line. The secure server is a centralized computer database that stores patient and implanted device data. These data are also immediately available for viewing by the physician on the secure Latitude website. Physicians and health care providers are notified of changes in patient status by an active monitoring system consisting of red and yellow alert notifications that are triggered by prespecified weight and device parameters. Red and yellow alerts used in this study are shown in Table 2. Red alerts are defined as conditions that could potentially leave the patient without device therapy, whereas yellow alerts are considered advisory. Detected alerts prompt a designated 24-hour Latitude customer support staff to notify the patient s designated clinician via telephone for red alerts and via fax for yellow alerts. Alerts are also available on the LATITUDE website for viewing by the clinician. Between scheduled in-clinic and post 6-month follow-up visits, alerts that occur may prompt the clinician to develop a course of medical intervention if necessary depending on type and urgency of the alert (Fig. 2). Intervention data will be captured on the MedNet Solutions Inc study website; the electronic data capture system used by research sites participating in RAPID-RF. Patient Population The RAPID-RF study will be conducted at approximately 100 centers. Consented patients who enroll must meet specific Table 1. Remote Active Monitoring in Patients with Heart Failure Study Data Collection at All Visits Patient Registration/Implant Visit 3-month Follow-up 6-month Follow-up* Post-6 Month Follow-ups*,y Unscheduled In-Clinic Visits Patient informed consent Inclusion/exclusion criteria Clinical history Current clinical information Current cardiovascular medications Minnesota Living with Heart Failure Questionnaire Global Assessment Tool Patient questionnaire Patient device data disk *If applicable. y Post 6-month follow-ups are defined as follow-ups to occur at 9, 12, 18, and 24 months after implant.

3 Remote Active Monitoring in Heart Failure Patients Saxon et al 243 Table 2. Remote Active Monitoring in Patients with Heart Failure Study Active Monitoring Alerts Alert Type Specific Alert Physician Notified Fig. 1. Remote Active Monitoring in Patients with Heart Failure study patients will be implanted with an radio frequencyeenabled cardiac resynchronization therapy defibrillator device (A), and are recommended to take their weight and blood pressure once daily. Patients will use a weight scale (B) and blood pressure monitor (C). Device, weight, and blood pressure data will be transmitted via the Latitude communicator (D) once daily through a standard telephone line (E) to be uploaded automatically to the Latitude secure server (F) where it is available for review by the clinician on the Latitude website. inclusion and exclusion criteria (Table 3). Patients with atrial fibrillation will not be excluded from study participation. Enrolled patients who meet standard device indications including a low ejection fraction of #35%, NYHA functional Class III or IV HF, QRS duration of $120 ms, and who are prescribed optimal pharmacologic therapy, unless otherwise indicated, will be implanted with a commercially available Guidant Contak Renewal 3 RF CRT-D device. n approval, future RF-enabled CRT-D devices that are compatible with the Latitude communicator may be included in the registry. Study End Points The primary objective of the trial is to characterize type and frequency of alert notifications, time from alert notification to medical intervention, and type of intervention implemented for activated alerts. An intervention may consist of a medication adjustment, in-clinic follow-up, emergency room visit, hospital visit, or may result in no action taken. The secondary objective is to assess NYHA class and quality of life changes over time, HF events, hospitalizations, mortality and device-collected data. At each visit, patients will be asked if they have had an HF event or hospitalization. Patients will be categorized as having an HF event if the patient has symptoms and signs Red Device battery has reached end of life Device Red High or low shock lead impedance Device Red High or low shock lead impedance detected Device when attempting to deliver a shock Red High or low right ventricular pacing lead Device impedance Red Low right ventricular intrinsic amplitude Device Red High voltage detected on shock lead during Device charge Red V-Tachy mode change from magnet Device Red V-Tachy mode set to value other than Device monitor þ therapy Red Possible device malfunction Device Red Device parameter error Device Yellow Weight-related Weight gain or loss of at least 2 lb over Healthfollowing 2 days or 5 lb in a week Yellow Device battery has reached elective Device replacement indicator Yellow Ventricular pacing leads including: Device High right ventricular intrinsic amplitude Low left ventricular intrinsic amplitude High left ventricular intrinsic amplitude Low left ventricular pacing lead impedance High left ventricular pacing lead impedance Yellow Atrial pacing leads including: Device Low atrial intrinsic amplitude High atrial intrinsic amplitude Low atrial pacing lead impedance High atrial pacing lead impedance Yellow Arrhythmia-related Shock therapy delivered to convert arrhythmia Accelerated arrhythmia episode Atrial tachycardia response detected for more than 24 hours Patient-triggered event stored Device consistent with HF (worsening NYHA class, orthopnea, dyspnea, edema, or gastrointestinal symptoms attributed to HF) and: (1) receives an augmented HF regimen with oral or intravenous therapy (intravenous diuretics, intravenous vasodilators, or intravenous inotropes), or an increase in oral diuretics in an outpatient setting such as an emergency ward or the equivalent within 24 hours; or (2) receives an augmented HF regimen with intravenous medications as listed during an in-hospital stay extending over 24 hours. To be considered a cardiac or nonecardiac-related hospitalization, a patient must be hospitalized for 24 hours and receive 1 or more of the above listed treatment therapies. Cardiac hospitalizations may include but are not limited to: HF, myocardial infarction, angina, syncope, cardiac procedure (percutaneous transluminal coronary angioplasty, coronary artery bypass graft/ valve surgery, heart transplant), arrhythmia, or complication of cardiac medication or procedure. Noncardiac hospitalizations include pulmonary, vascular, noncardiac chest pain, gastrointestinal, renal, cancer, hypovolemia, complication of noncardiac medication, and stroke.

4 244 Journal of Cardiac Failure Vol. 13 No. 4 May 2007 In Clinic Data Collection Registration/Implant Visit Complete Inclusion/Exclusion Criteria Collect clinical history and device data 3 & 6-Month In-Clinic Follow-up Visits Collect clinical outcome and device data At Home Data Collection Between In-Clinic Follow-ups Activated device-related and/or weight alerts may prompt physician medical intervention and treatment response 9, 12, 18, & 24 Month Follow-up Visits Collect clinical outcome measures Fig. 2. Remote Active Monitoring in Patients with Heart Failure study in-clinic and remote follow-up schedule. In addition to collecting clinical outcome data at follow-ups, patients will be asked to evaluate their HF symptoms on a weekly basis by answering 6 health status questions using their communicator from home (Table 4). Furthermore, a patient satisfaction questionnaire, to be answered at in-clinic follow-up, will assess patterns and ease of use of the Latitude communicator and home monitoring equipment (Table 5). Sample Size and Statistical Analysis Up to 1000 patients, with a minimum of 500 patients, was deemed sufficiently large to provide a representative sample of the general HF population that will allow accurate characterization of patient demographics, clinical attributes and event rates. For populations considered to be at high risk for HF hospitalizations, other remote-monitoring studies have reported 1-year HF hospitalization rates in the range of 30% to 40%. 4,19 If the population enrolled in this study has a hospitalization rate of only half of these observed rates (actual rates of 15% to 20%), following a minimum of 500 patients for an average of 6 months will provide Table 3. Study Inclusion/Exclusion Criteria Inclusion Criteria Patients who meet current indications for a CRT-D device Patients who have an analog telephone line to connect the Latitude communicator Patients who receive study components (Fig. 1) after implant Patients who are willing and capable of providing informed consent prior to implant and willing to participate in the Remote Active Monitoring in Patients with Heart Failure (RAPID-RF) Study Registry Patients who remain in the clinical care of a RAPID-RF investigator at approved centers Exclusion Criteria Patients who are expected to receive a heart transplant during the course of the study Patients who have or who will receive a tricuspid valve prosthesis during the course of the study Patients who have previously received an implantable cardiac resynchronization device (eg, biventricular pacemaker or biventricular implantable cardioverter defibrillator) Patients whose life expectancy is less than 12 months Patients who are enrolled in another observational registry or investigational study that could directly impact the treatment or outcome of the RAPID-RF Registry Patients who are younger than 18 years of age Patients who are pregnant or plan to become pregnant during the study Patients who are unable or refuse to comply with the protocol requirements approximately 40 to 50 HF hospitalizations. For annual event rates of 15% to 20%, enrolling between 500 and 1000 patients will provide a precision (defined as the half-width of the 95% confidence interval) of between 3.6% and 2.2%. Estimates of event rates for events that occur at higher incidence (eg, all-cause hospitalization) will be estimated with even better precision. The study is designed to stop enrollment before 1000 patients if the minimum number of patient enrollments and alerts are achieved. Alert minimums were set at 50 unique patients with arrhythmia-related alerts and 50 unique patients with weight alerts. Requiring a minimum of 50 unique patients with each category of alerts among a minimum of 500 enrolled patients will provide sufficient data to characterize the risk of having an alert in aggregate and for subgroups of patients; an alert rate minimum of 10% (50 alerts among 500 patients) can be estimated with a precision of 2.6% and additionally, a 10% alert rate will provide greater than 80% power to detect an odds ratio (odds of an alert versus no alert) between subgroups of 2.1 using a 5% level of significance. Patient demographics and clinical attributes will be summarized using descriptive statistics. Event rates will be calculated per 100 patient years of follow-up and the incidence of events and time to intervention based on events will be described with Kaplan-Meier Table 4. Latitude Communicator Health Status Questionnaire 1. Are you feeling unusually fatigued? Yes No 2. Have you felt faint or dizzy over the past No few days? nce Twice 3. Describe the swelling in your ankles, legs, or abdomen over the past few days. 4. Describe your ability to walk or climb stairs over the past few days. 5. How many pillows did you sleep with last night? 6. How often did you wake up breathless last night? Several times Decreased noticeably Remains about the same Increased noticeably I have no swelling Increased noticeably Remains about the same Decreased noticeably No difficulty None or or more Slept sitting up None nce A few times More than a few times

5 Remote Active Monitoring in Heart Failure Patients Saxon et al 245 curves. Generalized linear models and generalized estimating equations will be used to characterize changes in outcomes over time. The consistency of outcomes across clinical centers will be examined via stratified analyses. Study rganization Table 5. Patient Satisfaction Survey 1. How easy or difficult was it to set up the study components including the Latitude communicator, weight scale, and blood pressure monitor? 2. How easy or difficult is it for you to use the weight scale? 3. How easy or difficult is it for you to use the blood pressure monitor? 4. How easy or difficult is it for you to use the Latitude communicator? 5. Do you feel that continuous monitoring of your implanted device provides you with a sense of security? 6. Do you feel that continuous monitoring of your weight and blood pressure provides you with a sense of security? For the purpose of this study, each patient may be followed by both device- and health-following physicians. A device-following physician (typically an electrophysiologist) is responsible for managing the patient s device, including regularly scheduled device follow-ups. This physician is also responsible for managing red and the majority of yellow alert notifications. A healthfollowing physician (typically a cardiologist or HF specialist) is responsible for monitoring the patient s physiologic conditions through the use of weight, blood pressure, HF symptom-related questions, and relevant device-measured trends. Discussion Strongly agree Somewhat agree Neither agree or disagree Somewhat disagree Strongly disagree Strongly agree Somewhat agree Neither agree or disagree Somewhat disagree Strongly disagree utcomes for patients with advanced heart failure have improved dramatically. 20,21 This can be attributed to advances in pharmacothropics, particularly those resulting in neurohormonal blockade as well as management in heart failure clinics that provide continuing education for risk factor modification, diet, and weight monitoring. Cardiac resynchronization devices also improve outcomes in these patients and the widespread adoption of CRT therapy has introduced another layer of complexity in heart failure care. Electrophysiologists, as implanting and device follow-up physicians, have gained expertise in the operative and ambulatory follow-up of the HF patient. HF physicians have gained an understanding of how electrical therapies or new-onset arrhythmias can impact clinical outcomes. In most centers implanting CRT devices, partnerships have developed between subspecialties to everyone s mutual benefit, but this requires additional effort on the part of both treating physicians to communicate. 22 Communication technologies now present in implantable devices provide the opportunity to fully leverage advances in HF patient disease management to affect patient outcomes. The HF patient receiving CRT-D therapy is an ideal candidate for study from the advanced status of the disease and high risk of both HF and arrhythmia events. 8,9 ne major determinant of improved outcomes resulting from information transmitted remotely is how physicians and other health care providers respond to the information. The RAPID-RF study is designed to provide preliminary data related to disease management of the CRT-D recipient when communication capability placed in the device itself is used to monitor and transmit information related to the patient s overall disease status. References 1. 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