Author + information
- Received June 7, 2007
- Revision received October 16, 2007
- Accepted October 22, 2007
- Published online March 18, 2008.
- Robert C. Bourge, MD⁎,1,⁎ (, )
- William T. Abraham, MD, FACC†,2,
- Philip B. Adamson, MD, FACC‡,3,
- Mark F. Aaron, MD§,4,
- Juan M. Aranda Jr, MD∥,5,
- Anthony Magalski, MD¶,
- Michael R. Zile, MD#,6,
- Andrew L. Smith, MD, FACC⁎⁎,7,
- Frank W. Smart, MD††,8,
- Mark A. O’Shaughnessy, MD‡‡,
- Mariell L. Jessup, MD§§,9,
- Brandon Sparks, MS∥∥,10,
- David L. Naftel, PhD⁎,
- Lynne Warner Stevenson, MD¶¶,11,
- COMPASS-HF Study Group
- ↵⁎Reprint requests and correspondence:
Dr. Robert C. Bourge, Division of Cardiovascular Disease, 311 THT, 1900 University Boulevard, University of Alabama at Birmingham, Birmingham, Alabama 35294.
Objectives The purpose of this study was to determine whether a heart failure (HF) management strategy using continuous intracardiac pressure monitoring could decrease HF morbidity.
Background Patients with HF may experience frequent decompensations that require hospitalization despite intensive treatment and follow-up.
Methods The COMPASS-HF (Chronicle Offers Management to Patients with Advanced Signs and Symptoms of Heart Failure) study was a prospective, multicenter, randomized, single-blind, parallel-controlled trial of 274 New York Heart Association functional class III or IV HF patients who received an implantable continuous hemodynamic monitor. Patients were randomized to a Chronicle (Medtronic Inc., Minneapolis, Minnesota) (n = 134) or control (n = 140) group. All patients received optimal medical therapy, but the hemodynamic information from the monitor was used to guide patient management only in the Chronicle group. Primary end points included freedom from system-related complications, freedom from pressure-sensor failure, and reduction in the rate of HF-related events (hospitalizations and emergency or urgent care visits requiring intravenous therapy).
Results The 2 safety end points were met with no pressure-sensor failures and system-related complications in only 8% of the 277 patients who underwent implantation (all but 4 complications were successfully resolved). The primary efficacy end point was not met because the Chronicle group had a nonsignificant 21% lower rate of all HF-related events compared with the control group (p = 0.33). A retrospective analysis of the time to first HF hospitalization showed a 36% reduction (p = 0.03) in the relative risk of a HF-related hospitalization in the Chronicle group.
Conclusions The implantable continuous hemodynamic monitor-guided care did not significantly reduce total HF-related events compared with optimal medical management. Additional trials will be necessary to establish the clinical benefit of implantable continuous hemodynamic monitor-guided care in patients with advanced HF.
Advanced heart failure (HF) is characterized by frequent symptoms and hospitalizations resulting from fluid accumulation (1). To decrease the frequency of such events, patients must be closely monitored to detect changes in fluid volume status that may warrant modifying therapy. However, current volume assessment methods, such as physical examination or chest radiography, often correlate poorly with true volume status in patients with chronic HF (2,3). Even when fluid status is correctly assessed in the clinic, significant changes often occur in the ambulatory setting, where reliable information pertaining to volume status is lacking. Early signs of decompensation are often missed, along with the opportunity for timely intervention.
A totally implantable continuous hemodynamic monitor (ICHM) has been developed for outpatient HF management. The device (Chronicle, Medtronic Inc., Minneapolis, Minnesota) continuously measures and stores hemodynamic information that can be reviewed remotely. Chronic studies comparing intracardiac pressure measurements recorded by the ICHM with those obtained by a Swan-Ganz catheter have found the system to be safe, well tolerated, accurate, and stable over time (4–6). Early experiences using ICHM information in clinical practice supported the use of intracardiac pressures to manage volume status (7) and reduce HF-related hospitalizations (8).
The COMPASS-HF (Chronicle Offers Management to Patients with Advanced Signs and Symptoms of Heart Failure) trial was a randomized, single-blind, parallel-controlled trial designed to determine the clinical impact of an ICHM-based management strategy in patients with advanced HF already receiving optimal medical care.
Patients were eligible for enrollment in the study if they were at least 18 years old; had New York Heart Association (NYHA) functional class III or IV HF (regardless of ejection fraction); were managed in centers with an advanced HF program (participating investigators, sites, and coordinators are listed in the Online Appendix); received optimized standard medical therapy (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and a beta-blocker; all medications as tolerated) for at least 3 months before enrollment; and had at least 1 HF-related hospitalization or emergency department visit necessitating intravenous treatment (e.g., diuretic administration) within the previous 6 months. Patients were excluded from the study if they had severe chronic obstructive pulmonary or severe restrictive airway disease; pulmonary arterial hypertension; a major cardiovascular event (other than hospitalization) within 3 months before enrollment; known atrial or ventricular septal defects; tricuspid or pulmonary stenosis; mechanical right heart valves; a severe, noncardiac condition limiting 6-month survival; serum creatinine ≥3.5 mg/dl or chronic renal dialysis; were likely to undergo cardiac transplantation within 6 months of randomization; were receiving continuous positive inotropic therapy; were presently implanted with an incompatible pacemaker or implantable cardioverter-defibrillator (ICD); were receiving cardiac resynchronization therapy (CRT) that had not achieved optimal programming for 3 months; or were of childbearing age without reliable contraceptive measures. The institutional review board of each participating center approved the study protocol, and all patients provided written informed consent.
Patients with a preserved left ventricular ejection fraction (EF ≥50%) were included in the study for the following reasons: 1) HF patients with preserved EF account for approximately 50% of all HF hospitalizations (1); 2) the morbidity of such patients is comparable to that of HF patients with depressed EF, with a 50% 6-month re-hospitalization rate in both groups; and 3) HF patients with preserved EF have been difficult to manage (9,10).
Study design and procedure
Patients who met the entry criteria underwent the following baseline assessments: history and physical examination; chemistry profile; pulmonary function test; health care utilization in the 6 months before implantation; Minnesota Living with Heart Failure Quality of Life Questionnaire; NYHA functional classification; 6-min hall walk; echocardiogram; and 12-lead electrocardiogram. After initial evaluation, study participants underwent ICHM implantation, and if successful, were randomized for 6 months to the Chronicle or control group. Randomization schedules were created for patients based on EF (<50% or ≥50%) for each center. Clinicians had access to the hemodynamic information only in the Chronicle group. Beyond the 6-month randomization period, clinicians were granted full access to ICHM information in both groups.
During follow-up, clinicians reviewed the hemodynamic information of their Chronicle patients at least weekly to determine volume status. Patients were asked to chart daily weights and to document any adjustments made in daily medications. In addition, changes in patient symptoms and medications were documented by the enrolling site. At 1, 3, and 6 months post-implantation, all study patients returned for reassessment of their physical status, NYHA functional class, medications, health care use, and adverse events. At the 3- and 6-month visits, the quality-of-life questionnaire and 6-min hall walk were repeated.
An independent Clinical Events Adjudication Committee, blinded to patients’ randomization assignment, adjudicated all major events, including hospitalizations, emergency department visits, and urgent clinic visits.
The design of the COMPASS-HF trial was single blind because clinicians needed to periodically review patient-specific hemodynamic information and implement appropriate individual treatment plans in the Chronicle group. To maintain patient blinding during the randomized follow-up period, several measures were incorporated into the study protocol. First, patients in both groups were asked to transmit their ICHM information at least weekly. Second, to ensure that nonblinded caregivers did not inadvertently disclose the patient’s randomization assignment, pre-crafted standardized clinician communication scripts were used. These scripts included questions related to standard HF management (e.g., shortness of breath, weight gain), but did not include any reference to intracardiac pressures. After any telephone contact with patients (clinician-initiated or patient-initiated), clinicians completed a telephone communication form. Third, because clinician review of hemodynamic information was expected to increase the frequency of calls in the Chronicle group (e.g., change in pressure that might warrant a medication change), pre-determined call schedules were generated for the control patients. During the study, additional random call schedules were used in the control group to match the increased frequency of communications in the Chronicle group.
ICHM system description
The ICHM system (Model 9520, Medtronic) consists of: 1) a programmable device that processes and stores information and is similar in appearance to the pulse generator of a pacemaker; and 2) a transvenous lead (model 4328A, Medtronic) that has a sensor incorporated near its tip to measure intracardiac pressure. The implantation procedure is similar to that of a single-lead pacemaker system, with the device positioned subcutaneously in the pectoral area and the lead positioned transvenously in the right ventricular outflow tract or septum.
The ICHM is capable of continuously monitoring and storing heart rate, body temperature, patient activity, right ventricular systolic and diastolic pressure, maximal positive and negative rate of change in right ventricular pressure (dP/dt), right ventricular pre-ejection and systolic time intervals, and estimated pulmonary arterial diastolic pressure (ePAD) (11). The ePAD is defined as the right ventricular pressure at the time of pulmonary valve opening, which occurs at the time of maximal dP/dt (7,11,12). A strong correlation (r = 0.84) has been shown to exist between ePAD and actual pulmonary artery pressures measured under a variety of physiological conditions (5,12,13).
Because the ICHM records absolute pressure, all pressure data were corrected for barometric pressure using a small external pressure reference device (model 2955HF, Medtronic) carried by the patient.
ICHM data generation and flow
The ICHM measures all pressure parameters on a beat-to-beat basis, but ultimately commits to memory a smaller dataset based on a programmable storage interval, most often set to approximately 8.5 min. For each pressure parameter, the median as well as the sixth and 94th percentiles of all measurements taken within this pre-set time interval are determined and stored. All patients were instructed to transmit information from the ICHM at least weekly using a home monitor that interrogates the device via a standard handheld radio frequency wand and transmits the data through a telephone line to a secure server. Clinicians could access the data transmitted by their patients on the ICHM Web site using conventional Internet access.
ICHM data review and use
Hemodynamic data were available for clinical management only in the Chronicle group. Review of the pressure information occurred at least once per week, usually in conjunction with data transmission from the patient’s home. The Web site automatically concatenates new data received from the device with data from previous transmissions and provided visual representation of the data in the form of trends over time (Figure 1). The ultimate goal of ICHM data review was to determine the patient’s pressure status remotely and intervene appropriately before an HF-related event.
End points and statistical analysis
For the primary effectiveness end point, we hypothesized that the Chronicle group would have a 30% lower rate of combined HF-related events (hospitalizations, emergency department and urgent clinic visits requiring intravenous therapy) compared with the control group. The event rate in the control group was estimated to be 1.2 per 6 patient-months, determined from previous ICHM studies and other published HF trials (14–17). A cumulative randomized follow-up of 1,354 patient-months was required to show significance in event rates between the 2 groups with 80% power (alpha = 0.05). A total of 274 patients were randomized to satisfy sample size requirements and attrition assumptions. The primary effectiveness end point was analyzed using a negative binomial regression (18). Additionally, a retrospective analysis of the relative risk of a HF hospitalization was performed using a Cox proportional hazards regression model.
For the primary safety end points, we hypothesized that at 6 months, the freedom from system-related complications would be ≥80%, and the freedom from pressure sensor failure would be ≥90%. A system-related complication was defined as any adverse event that was related to the system (ICHM and pressure sensor lead) and was either treated with invasive means or resulted in the death of a patient, the explant of the device or caused permanent loss of significant function of the system. Because the integrity of the pressure data is related to the performance of the pressure sensor lead, it was deemed important to designate pressure sensor lead failure as a separate safety end point. The sample size requirement for testing the primary effectiveness end point (1,354 patient months) was more than adequate to test both primary safety end points. The primary safety end points were analyzed using the Kaplan-Meier method.
An independent Data Monitoring Committee reviewed all of the safety and effectiveness data. Group sequential methods were used to create predetermined decision boundaries using O’Brien and Fleming shape parameters (19). The level of significance for the final analysis was 0.048 for the primary efficacy end point and 0.049 for the primary safety end points.
A total of 301 patients were enrolled in the study. Twenty-four patients exited the study before device implantation attempt: 2 patients died before scheduled implant, 7 withdrew consent, 6 were withdrawn by the investigator, 6 had study entrance criteria violations, and 3 patients could not undergo implantation because of anatomical considerations. The remaining 277 patients underwent an implant attempt, with 274 patients (99%) with successful implantations. The 3 unsuccessful implantations were caused by entanglement of the lead in the tricuspid valve, complete heart block, and inability to gain venous access. These 274 patients were then randomized to either the Chronicle (n = 134) or control group (n = 140) (Fig. 2). Clinical characteristics of randomized patients were well balanced between the 2 groups (Table 1), with the exception of baseline diuretic use (93% in the Chronicle vs. 99% in the control group). However, by day 17 of randomization, diuretic use was 99% in both groups.
Of the 274 randomized patients, 245 completed their 6-month follow-up, accruing 1,620 patient-months of randomized follow-up. Of the 29 patients who exited the study during the randomization period, 16 were in the Chronicle group (13 patients died, 2 patients withdrew consent, and 1 patient transferred care), and 13 were in the control group (11 patients died, 1 was lost to follow-up, and 1 patient was withdrawn because of lead dislodgement). Implementation of the study’s rigorous blinding protocols, as described earlier, resulted in an equivalent average number of telephone calls between patients and clinics over the 6-month randomization period (24.7 calls/patient in both groups).
Primary safety end points
Both primary safety end points were met. Of the 277 patients in whom an implantation was attempted, 23 patients experienced a total of 24 complications for a complication-free rate of 91.5% (lower 1-sided 95% confidence bound of 88.7%). All but 1 of the 24 complications were related to the lead. Of the 23 lead-related events, 15 were lead dislodgements, all of which were either repositioned or replaced. The 1 nonlead-related complication was caused by premature battery failure, which was resolved by an ICHM system replacement. Overall, 20 of the 24 (83%) system-related complications were successfully resolved and resulted in a fully functional ICHM system. No sensor failures occurred in the 274 randomized patients.
During the initial implantation, there were 6 procedure-related and 6 device-related complications in 12 patients that prolonged the initial hospitalization by a total of 10 days in 6 patients. After implantation, there were 11 hospitalizations for device-related complications and 4 hospitalizations for procedure-related complications that resulted in a total of 40 additional hospitalization days in 13 of the 274 successful implantation patients.
Primary efficacy end point
There were 84 HF-related events in 44 patients in the Chronicle group, and 113 in 60 patients in the control group, for an event rate of 0.67 and 0.85 per 6 patient-months, respectively (Fig. 3). The primary efficacy end point was not met because the 21% reduction in the rate of HF-related events in the Chronicle group was not statistically significant (p = 0.33). Nonhospitalization HF-related events were equally rare in both the Chronicle and control groups (10 vs. 11 emergency department visits and 2 vs. 3 urgent care visits, respectively). Specific attention was also paid to events such as hypovolemia, which could occur because of overdiuresis. There were 6 events in 6 patients in the Chronicle group caused by hypovolemia, compared with 10 events in 9 patients in the control group.
Retrospective efficacy analysis
A retrospective efficacy analysis was performed using the time to first HF-related hospitalizations after randomization (Fig. 4). During the randomized period, 37 patients in the Chronicle group were hospitalized for HF, compared with 57 patients in the control group (hazard ratio 0.64, 95% confidence interval 0.42 to 0.96, p = 0.03). This represented a 36% reduction in the relative risk of an HF-related hospitalization in the Chronicle group. The reduction in the relative risk of an HF-related hospitalization was comparable in the groups with EF ≥50% and <50%.
Treatment of patients with HF has improved dramatically over the last 2 decades. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, aldosterone antagonists, and more recently CRT and ICDs, have all been shown to improve patient outcomes (20). Despite the progress in these therapies, the number of hospitalizations for worsening HF continues to increase (21). Symptoms associated with hospitalization are most often attributable to increased filling pressures and the resultant pulmonary and systemic venous congestion (22). To reduce HF hospitalizations, improved strategies for outpatient monitoring and fluid management are urgently needed. There has been concern, however, that knowledge of ventricular filling pressures may lead to intensification of diuretic therapy and an increase in events attributable to relative hypovolemia.
The COMPASS-HF study was a unique study that implemented and tested a novel HF management strategy using objective ICHM-derived information on a patient’s dynamic intracardiac pressure status in the ambulatory setting. It is important to recognize that this trial evaluated a novel management strategy using existing evidence-based therapies for HF, rather than a new therapeutic modality.
Although there was 21% reduction in the total event rate in the Chronicle group compared with the control group, the difference was not significant and the primary efficacy end point was not met (Fig. 3). It is possible that the study was underpowered to show a significant difference in event rates between the 2 groups. The sample size was estimated based on an event rate of 1.2 per 6 patient-months in the control group, but the actual event rate in the control group was only 0.85 per 6 patient-months. This lower event rate can be partially attributed to the intensive contact schedule between patients and clinics in the control group (almost once per week) that matched the contact schedule observed in the Chronicle group. Because frequent patient contact with HF management teams reduces hospitalizations (23,24), this increased level of interaction likely contributed to the lower than expected event rate observed in the control group and reduced the power of the study to show a significant benefit of the ICHM.
Despite the lack of a significant reduction in the combined event rate in the Chronicle group, a retrospective analysis showed that there was a 36% reduction in the relative risk of a first HF-related hospitalization (Fig. 4), and this suggests the ICHM may have some clinical value. This analysis was based on a subset of total HF-related events (48% were first hospitalizations), and this may partially account for the difference between this end point and the primary end point. Although the time to first HF-related hospitalization was not a pre-specified end point, this end point has been used in other HF trials (25,26).
Until now, HF management in the ambulatory setting has been limited to clinical assessment during outpatient visits and the evaluation of symptoms and weight changes as reported by the patient from home. However, the ICHM provides additional hemodynamic information that may improve HF management. Managing patients using the ICHM information included defining an optimal pressure range for each patient. When hemodynamic data deviated from this range, therapy was adjusted with the goal of restoring pressure to the optimal range. Indeed, patients in the Chronicle group had 28% more adjustments in their therapies than patients in the control group, despite an equivalent frequency of patient contacts to evaluate symptoms and weight changes. The majority of these changes were in diuretic doses, which were changed 54% more often in the Chronicle group. Although these changes in diuretic doses did not significantly reduce the rate of all HF-related events, there was also no increase in events that might be attributed to overdiuresis in the Chronicle group.
Given the amount of information provided by the ICHM, there is the question of training and widespread adoption of this technology. A learning curve is to be expected in association with the routine integration of intracardiac pressures into clinical practice. Moreover, the ICHM generates large amounts of data in each patient that require review. However, the trial experience showed that even high-enrolling centers were able to successfully manage the data during the required follow-up period and beyond. Some participating centers had staffing capacity that may not reflect the mainstream clinics caring for HF patients, and this may have facilitated management of the ICHM data. Hopefully, future data management tools, including automated algorithms and potentially third-party monitoring services, may alleviate some of these concerns.
In the COMPASS-HF study, clinicians were required to use the ICHM information to guide patient-specific care; thus, a double-blind design was not possible. Because all patients received a device to control for a potential placebo effect, the study lacked a concurrent control arm without an implanted device. Because the COMPASS-HF study was conducted primarily at sites with dedicated HF programs, the ICHM experience has not yet been generalized to the community setting. Furthermore, it is important to recognize that all patients in both groups required at least 1 hospitalization day to implant the ICHM.
In patients with moderate to severe HF, the addition of an ICHM to optimal medical management did not significantly reduce the rate of all HF-related events. Additional trials will be necessary to establish the clinical benefit of ICHM-guided care in this patient population.
The authors thank Janice Hoettels, PA-C, and Jane Moore for their editorial support in the preparation of this article. In addition, the authors thank Tom Bennett, PhD, and Amy Roettger, RN, for management of clinical operations related to the COMPASS-HF study.
For a list of the participating investigators, sites, and coordinators, please see the online version of this paper.
↵1 Dr. Bourge received a research grant from, honoraria from, and was a consultant/advisory board member for Medtronic Inc.
↵2 Dr. Abraham received a research grant from, honoraria from, and was a consultant/advisory board member for Medtronic Inc.
↵3 Dr. Adamson received research grants from Sigma-Tau, Medtronic Inc., and Cardiomems; honoraria from Medtronic Inc. and Sigma-Tau; and was a consultant/advisory board member for Medtronic Inc., Cardiomems, GlaxoSmithKline, and Sigma-Tau.
↵4 Dr. Aaron received a research grant from Medtronic Inc., was a Speakers’ Bureau member for GlaxoSmithKline, received honoraria from Medtronic Inc., and was a consultant/advisory board member for Medtronic Inc.
↵5 Dr. Aranda received honoraria from and was a consultant/advisory board member for Medtronic Inc.
↵6 Dr. Zile received a research grant from and was a consultant/advisory board member for Medtronic Inc.
↵7 Dr. Smith was a consultant/advisory board member for Medtronic Inc.
↵8 Dr. Smart was a Speakers’ Bureau member for Scios and BioSite, and received honoraria from Scios, BioSite, and Thoratec.
↵9 Dr. Jessup was a Speakers’ Bureau member for Medtronic Inc., GlaxoSmithKline, and AstraZeneca and was a consultant/advisory board member for GlaxoSmithKline, Ventracor, Medtronic Inc., and ACORN.
↵10 Dr. Sparks has ownership interest in and is employed by Medtronic Inc.
↵11 Dr. Stevenson received a research grant from, honoraria from, and was a consultant/advisory board member for Medtronic Inc.
This study was supported by Medtronic Inc., Minneapolis, Minnesota.
- Abbreviations and Acronyms
- cardiac resynchronization therapy
- ejection fraction
- estimated pulmonary artery diastolic pressure
- heart failure
- implantable cardioverter-defibrillator
- implantable continuous hemodynamic monitor
- New York Heart Association
- Received June 7, 2007.
- Revision received October 16, 2007.
- Accepted October 22, 2007.
- American College of Cardiology Foundation
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