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European Journal of Heart Failure 2008 10(9):907-916; doi:10.1016/j.ejheart.2008.06.016
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© 2008 European Society of Cardiology

Can monitoring of intrathoracic impedance reduce morbidity and mortality in patients with chronic heart failure? Rationale and design of the Diagnostic Outcome Trial in Heart Failure (DOT-HF)

Frieder Braunschweiga,*, Ian Fordb, Viviane Conraadsc, Martin R. Cowied, Guillaume Jondeaue, Josef Kautznerf, Maurizio Lunatig, Roberto Munoz Aguilerah, Cheuk Man Yui, Monique Marijianowskij, Martin Borggrefek, Dirk J. van Veldhuisenl DOT-HF steering committee and investigators

a Karolinska Institutet, Department of Cardiology, Karolinska University Hospital Stockholm, Sweden
b Robertson Centre for Biostatistics University of Glasgow, Glasgow, UK
c Antwerp University Hospital, Department of Cardiology Edegem, Belgium
d Imperial College London, UK
e Service de Cardiologie, Hôpital Bichat, AP-HP, Univesrsité Paris VII, INSERM U698 Paris, France
f Institut Klinicke a Experimentalni Mediciny (IKEM) Prague Czech Republic
g Department of Cardiology A.O. Niguarda Cà Granda, Milan, Italy
h Department of Cardiology, Hospital Infanta Leonor Madrid, Spain
i Prince of Wales Hospital, Institute of Vascular Medicine Hong Kong, China
j Medtronic Bakken Research Center CRDM, Maastricht, The Netherlands
k 1st Department of Medicine-Cardiology, University Hospital Mannheim Mannheim, Germany
l Department of Cardiology, University Medical Center Groningen Groningen, The Netherlands

* Corresponding author.Department of Cardiology, Karolinska University Hospital, S-171 76 Stockholm, Stockholm, Sweden. Tel.: +46 8 51771629; fax: +146 8 311044. E-mail address: frieder.braunschweig{at}karolinska.se (F. Braunschweig).


   Abstract
Top
 Abstract
1. Background
 2. Methods
 References
 
Background: Chronic heart failure is associated with frequent hospitalisations which are often due to volume-overload decompensation. Monitoring of intrathoracic impedance, measured from an implanted device, can detect increases in pulmonary fluid retention early and facilitate timely treatment interventions.

Objective: The DOT-HF trial is designed to investigate if ambulatory monitoring of intrathoracic impedance together with other device-based diagnostic information can reduce morbidity and mortality in patients with chronic heart failure who are treated with cardiac resynchronization therapy (CRT) and/or an implantable defibrillator (ICD).

Methods: Approximately 2400 patients will be randomised in a 1:1 fashion to a management strategy with access to the diagnostic information from the implantable device ("access arm"), or a "control arm", where this information is not made available. Study subjects fulfil standard indications for CRT and/or ICD as outlined in current guidelines. In the access arm, a fluid alert algorithm is used to give early warning of decreasing intrathoracic impedance indicating a high risk of an impending volume-overload decompensation. The primary endpoint of DOT-HF is the composite of all-cause mortality or heart failure hospitalisation. Secondary and exploratory endpoints include all-cause mortality, the impact on total health care utilization, quality of life and cost effectiveness. The study is expected to close recruitment during 2010 and to report in 2012.

Key Words: DOT-HF trial • Congestive heart failure • Monitoring • Cardiac resynchronization • Implantable defibrillator • Bioimpedance

Received February 13, 2008; Revised April 16, 2008; Accepted June 24, 2008


   1. Background
Top
 Abstract
 1. Background
2. Methods
 References
 
Heart failure is among the most common causes of hospital admission [1,2] and continues to be associated with poor survival despite recent advances in medical and device therapies [3,4]. A large proportion of heart failure related hospitalisations are due to fluid accumulation and volume-overload typically associated with symptoms of central and peripheral congestion such as dyspnoea, tiredness and pulmonary oedema or ankle swelling [1,5-7]. A patient who is hospitalised for decompensated heart failure has a dismal prognosis with a high risk of early death or hospital readmission approximating 35% within 60 days [5,6,8]. This adverse outcome was recently corroborated by data from the CHARM program showing a more than threefold increased mortality risk in patients discharged after a heart failure hospitalisation [9] and another trial in patients hospitalised for acute heart failure reported a one year mortality of 25% [10]. Moreover, heart failure hospitalisations represent the largest component of the high treatment costs for heart failure [11].

In the majority of cases, heart failure decompensations occur in patients who already have an established diagnosis of chronic heart failure [5,7]. Careful surveillance of the fluid status is, therefore, important in the day-to-day management of patients with heart failure in order to maintain fluid balance and to avoid volume expansion, as recommended in international guidelines [12,13]. However, typical clinical signs and symptoms of heart failure usually occur late in the course of decompensation and are largely unreliable in the routine follow-up of chronic heart failure patients [14,15]. Moreover, daily measurements of body weight, a mainstay of heart failure outpatient management, have poor sensitivity to predict clinical deterioration [16].

Recent studies using implanted monitoring technology have demonstrated that acute heart failure decompensation is often preceded by a gradual accumulation of fluids, reflected by an increase of cardiac filling pressures over several days or weeks [17]. These observations suggest that implanted sensors for continuous monitoring of volume load and fluid retention could be clinically useful to detect early signs of an impending cardiac decompensation and, thus, enable timely treatment interventions aimed at avoiding overt heart failure and severe clinical events requiring hospitalisation. It is also conceivable that continuous monitoring improves patient compliance and adherence with medication and other guideline recommended therapeutic measures, which has been shown to be associated with a decrease in clinical events [18].

1.1. Devices in heart failure
Electrical devices for cardiac resynchronization therapy (CRT), the implantable cardiac defibrillator (ICD) or the combination of both (CRT-D) are today firmly established as effective means to prolong survival in patients with chronic heart failure [19-22]. Moreover, CRT has been demonstrated to improve cardiac function, exercise capacity and quality of life in patients with drug-refractory heart failure and prolonged QRS duration [23,24]. Accordingly, the number of heart failure patients treated with such devices has increased rapidly over recent years and now constitutes a substantial portion of subjects followed at specialized heart failure clinics. However, despite the improvements brought by devices, these patients are still at considerable risk for heart failure hospitalisation or death, as indicated by the annual event rates in the treatment arms reported in large scale heart failure device trials [19-21]. Consequently, the management of heart failure patients with implanted devices still needs to be improved and remains a clinical challenge for multidisciplinary collaboration.

1.2. Implanted monitoring features
Apart from delivering effective therapy, electrical heart failure devices also offer a number of diagnostic features which allow monitoring of variables with potential value for heart failure management. Intrathoracic impedance, measured as the electrical impedance between a right ventricular pacing- or defibrillation-lead and the device-can, offers a novel tool to track changes in the thoracic fluid content [25]. Based on the principle that increased pulmonary fluid retention causes a drop in intrathoracic impedance, this technology has been incorporated into pacemakers or ICDs for continuous monitoring of the fluid status in patients with chronic heart failure. Yu and co-workers, analyzing the feasibility of this concept in the MIDHeFT study, demonstrated that intrathoracic impedance is inversely correlated with the pulmonary capillary wedge pressure and the patient's fluid balance [26]. In their study, all hospitalisations for volume-overload due to heart failure were associated with a decrease in intrathoracic impedance prior to admission. Notably, impedance started to decrease an average of 18 days before hospital admission and at a mean of 15 days prior to the occurrence of clinical symptoms. These findings point towards a large time window between the early detection of an imminent decompensation and its final clinical manifestation. Based on these findings, a fluid detection algorithm was developed to give an alert at a certain level of impedance change indicating a high risk for a subsequent heart failure hospitalisation.

Preliminary data from clinical studies suggest that intrathoracic impedance monitoring may in fact improve the ambulatory management of patients with chronic heart failure. An observational study with OptiVol® reported that the system detected clinical heart failure deterioration with 60% sensitivity and with a positive predictive value of 60% during short-term follow-up [27]. In a small case-control study, significant reductions in heart failure hospitalisations were observed over 2 years in patients with access to alerts of potential fluid build-up with OptiVol® compared with patients without access to such alerts [28]. Further clarification as to the sensitivity of the fluid detection algorithm in predicting HF related hospitalisations is expected to arise from the ongoing Sense-HF study (ClinicalTrials.gov identifier NCT00400985 [ClinicalTrials.gov] ).

Another approach to heart failure monitoring, continuous measurement of intracardiac pressures from an implanted device, was recently evaluated in the COMPASS-HF study showing a non-significant 21% decrease of all heart failure related events after 6 month of follow-up [29]. Yet, a retrospective analysis of the time to first heart failure hospitalisation showed a significant risk reduction by 36%. This technology, used as an integral part of an ICD, is now being evaluated in a larger clinical trial [30]. Moreover, monitoring of heart rate, a fundamental physiological variable with prognostic importance in heart failure and other cardiovascular disease [31,32], may be of particular interest in this patient group and the chronic heart rate profile has been shown to correlate with functional improvement and structural myocardial changes by CRT [33]. Heart rate variability (HRV), an established measure of the autonomic nervous tone, is related to the progression of heart failure [34,35]. Measured from a CRT device, HRV differs significantly between patients in different NYHA classes [36] and is significantly lower in patients at high mortality and hospitalisation risk [37]. Daily physical activity may reflect patients' exercise tolerance similarly to other exercise tests used for the assessment of heart failure. In CRT patients, physical activity is related to functional class and reflects the clinical improvement achieved by CRT implantation [36]. Trend changes of these variables provide potentially useful information for clinicians as they may reflect a change in disease severity and suggest modifications in treatment or the intensity of clinical follow-up.

Despite these encouraging results, it needs to be stated that the experience with device-based monitoring is still in an early stage and that the clinical effectiveness of this strategy in a large population is not known. Furthermore, an increased level of patient surveillance by itself does not necessarily decrease the burden of heart failure related hospitalisation as recently shown in studies assessing the value of intensive nurse support [38] or home telemonitoring [39]. Finally, early alerts on increased fluid retention may lead some physicians to over-prescribe heart failure medications with a potential risk for treatment related adverse effects.

DOT-HF is a large scale randomised clinical trial to investigate, whether the clinical outcome of patients with an implanted heart failure device can be improved by using the information from intrathoracic impedance monitoring, and other inbuilt diagnostic features for patient management. Parallel to DOT-HF, the Prospective, Randomized Evaluation of Cardiac Compass® with OptiVol® in the Early Detection of Decompensation Events for Heart Failure (PRECEDE-HF) trial started in United States and Canada (ClinicalTrials.gov identifier NCT00510198 [ClinicalTrials.gov] ). Both trials are similar in design and sponsored by Medtronic Inc, (Minneapolis, MN, USA). The present paper describes the rationale and study design of DOT-HF.


   2. Methods
Top
 Abstract
 1. Background
 2. Methods
References
 
2.1. Study purpose and population
The DOT-HF trial is designed to investigate whether monitoring of intrathoracic impedance using the OptiVol® fluid status algorithm together with other device-based diagnostic information can reduce morbidity and/or mortality in patients with chronic heart failure who are treated with a CRT and/or ICD device. The hypothesis is that OptiVol® fluid status monitoring and the fluid alert can be useful to detect impending fluid accumulation at an early stage. This may facilitate early treatment interventions that may prevent further progression to overt cardiac decompensation and, thus, decrease the incidence of hospitalisation for decompensated heart failure and the risk of death.

2.2. Monitoring of intrathoracic impedance and other diagnostic features
Fluid status monitoring by OptiVol® is based on calculations of the average daily intrathoracic impedance measured between a right ventricular pacemaker- or defibrillation-lead and the device can. This technology is currently available in the Medtronic InSync SentryTM (CRT-D), ConcertoTM (CRT-D), and VirtuosoTM (ICD) devices (Medtronic Inc, Minneapolis, MN, USA). According to the principle that intrathoracic impedance drops with an increase in pulmonary fluid content, this information can be used to track changes in the patient's fluid status over time. OptiVol® also compares the actual patient impedance with a reference impedance that is derived from a moving average algorithm. When daily impedance values consistently fall below the reference impedance, the difference accumulates in the OptiVol® fluid index. If the OptiVol® fluid index crosses a certain threshold, an alarm will be triggered indicating that the patient is at increased risk for a subsequent heart failure decompensation and appropriate therapeutic interventions can be initiated. Fig. 1 shows a patient example with trend data on intrathoracic impedance and the OptiVol® fluid index.


Figure 01
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  		Fig. 1 Patient example with trend data for intrathoracic impedance (lower panel) and the corresponding OptiVol® fluid index (upper panel). a) During the first weeks, intrathoracic impedance gradually increases possibly reflecting a decreasing pulmonary fluid content following the initiation of cardiac resynchronization therapy and the post-operative resorption of fluids in the device pocket. b) There is a decrease in intrathoracic impedance leading up to c) crossing of the OptiVol® fluid index threshold indicating increased pulmonary fluid retention and a possible risk for subsequent cardiac decompensation. Upon threshold crossing, the patient received an audible alert by the device and presented to his physician 2 days later with minor symptoms and signs of deteriorated heart failure. An extra dose of oral furosemide was given for 2 weeks helping to normalize patient status and impedance values.

 
This threshold crossing can be notified in three different ways: either by an audible tone from the device, by using a hand held patient indicator (patient-check) or by a patient home monitor that connects through wireless communication to the implanted device. An alarm threshold of 60 Ohm-days is preset by the manufacturer, based on sensitivity and specificity calculations from the MIDHeFT study [26]. This threshold yielded the greatest diagnostic accuracy to predict a subsequent hospitalisation for decompensated heart failure, with a sensitivity of 77% and 1.5 so called "false positive" alerts per patient per year. Threshold crossing was observed 13.4±6.2 days before the clinical event. At the time of an OptiVol® alert, the typical clinical signs of heart failure, usually appearing relatively late in the course of volume-overload decompensation, may be not fully developed or even present. In accordance with the concept of "treating congestion early", such alerts are considered useful to direct the clinician's attention towards a patient at risk for a subsequent deterioration, and should not be regarded as necessarily "false". Occasionally, an OptiVol® alert may indicate other clinical conditions with impact on intrathoracic impedance such as pulmonary infection, pleural or pericardial effusion, lead dislodgement or oedema in the device pocket.

In addition, devices used in the present study provide a number of other diagnostic features (Table 1). Together with the impedance trends and the OptiVol® fluid index, these data are presented in the Cardiac Compass® report and printed out at the time of device interrogation. Optionally, if available at the study site, diagnostic device information can also be transmitted remotely to health care providers using Web-based technology (the CareLink® System) [40]. The data are transmitted over a telephone line to a central data server, where clinicians can access the information on a secure website.


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  		Table 1 Diagnostic trend information provided to clinicians for patients randomised to the "access arm"

 
2.3. Study population
Approximately 2400 patients will be enrolled in up to 120 centres in Europe and the Middle-East, as well as in selected sites outside this region. Study duration is expected to last approximately five years dependent on patient enrolment and event rates. Patients will be randomised (open label) in equal numbers to the "access arm", using a management strategy with availability of the OptiVol® fluid alert and access to the diagnostic information from the implantable device, or a "control arm", where this information is not available for the treating physician or the patient.

Study inclusion and exclusion criteria are given in Table 2. Patients included in DOT-HF have been implanted with a CRT, CRT-D or ICD device providing OptiVol® fluid status monitoring and Cardiac Compass® capabilities. Patients meet the standard clinical indications for device therapies in chronic heart failure as recommended by current guidelines [12,13,41,42]. In addition, to ensure the selection of patients with a substantial risk for decompensation, a previous hospitalisation for heart failure within 12 months prior to device implantation is required. The use of monitoring applications investigated in DOT-HF does not represent a primary indication for device implantation.


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  		Table 2 Study inclusion and exclusion criteria

 
Patients cannot be included within 90 days after open heart surgery since post-operative wound healing may affect intrathoracic impedance values. The impact of severe chronic obstructive pulmonary disease on intrathoracic impedance is yet not fully understood and patients with this condition are excluded. Likewise, DOT-HF will not include patients with serum creatinine ≥2.5 mg/dL and those with primary pulmonary hypertension or complex and uncorrected congenital heart disease. Furthermore, patients are excluded if their management includes the use of any other automatic or interactive method for remote patient surveillance ("telemedicine") to determine, monitor or alert on weight changes or other signs and symptoms of heart failure.

2.4. Study design
Fig. 2 illustrates the basic study design. Patients can be enrolled up to 6 months after device implantation. Randomisation will take place 1 month after enrollment to allow for post-operative stabilization of the patient and resolution of possible pocket oedema. Autocalibration of the impedance reference takes another 3 days. As baseline characteristics of patients receiving an ICD without resynchronization capabilities for primary prevention of sudden cardiac death may differ from those implanted with a CRT device for treatment of medically refractory heart failure, randomisation will be stratified by centre and device type, ie CRT, CRT-D or ICD.


Figure 02
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  		Fig. 2 Study design of DOT-HF.

 
Detailed information on typical signs and symptoms of heart failure are collected at enrollment, randomisation and scheduled follow-up visits at 3 months, 6 months and every 6 months after randomisation until study closure or subject exit. These scheduled follow-ups include visits to clinicians responsible for both electrophysiological and heart failure related aspects of care. Additional data will be collected at all unscheduled office visits, emergency department visits, urgent visits, hospitalisations, medical interventions, telephone contacts and device system modifications. Data will be collected on all adverse events, study deviations and study exit or death.

2.5. Primary study endpoint
The primary objective of DOT-HF is to assess if heart failure patient management using OptiVol® fluid status monitoring and other diagnostic information from the Cardiac Compass Report on top of standard clinical assessment ("access arm"), leads to a reduction in the combined endpoint of all-cause mortality or heart failure hospitalisation as compared to standard clinical assessment alone ("control arm", Table 3). A composite of all-cause mortality and hospitalisation for heart failure is chosen as the primary study endpoint since both these events substantially contribute to the burden of illness in heart failure. Hence, significant improvements by implementing management strategies with access to device-based diagnostic information are expected to impact the combination of these endpoints.


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  		Table 3 List of primary and secondary study objectives

 
In DOT-HF, heart failure hospitalisation is defined as a non-elective hospital admission for worsening heart failure which is associated with signs and symptoms of congestion, requires at least one overnight stay in hospital and is treated with an augmentation of oral diuretic or the administration of intravenous diuretics, vasodilators, inotropes, or other parenteral therapy. Moreover, a hospitalisation for heart failure can be associated with signs and symptoms of hypoperfusion indicated by organ compromise ("low-output"). Clinically relevant events leading to urgent or unscheduled emergency department or office visits will be recorded and analyzed as outlined in the secondary endpoint section.

2.6. Secondary and exploratory study endpoints
Secondary endpoints of DOT-HF (Table 3) include the single components of the primary endpoint with all-cause mortality representing the least biased measure of outcome. While the primary endpoint analysis will be based on time-to-first-event statistics, a secondary endpoint addresses simultaneously the time from randomisation to each heart failure hospitalisation or death. This analysis accounts for the differential contribution of hospitalisation and death to study outcome as a patient's death will generate a singular endpoint, whereas surviving patients may suffer from repeated hospitalisation events. Furthermore, the combined endpoint of all-cause mortality and cardiovascular hospitalisations including coronary syndromes, arrhythmia, syncope, and stroke, will be evaluated.

A management strategy using monitoring features and alert-triggered early interventions may cause a change from major hospitalisation events to minor outpatient contacts. Therefore the impact on overall health care utilization in the access arm compared with the control arm will be an important exploratory outcome of DOT-HF. This analysis will cover all hospitalisations and emergency department visits as well as scheduled or unscheduled office visits or phone calls due to fluid alerts, review of Cardiac Compass® trends, device related issues or worsening signs or symptoms of cardiac decompensation. Furthermore, the effect on all occasions of worsening heart failure will be evaluated, counting all heart failure related hospitalisation, emergency department visits and urgent visits.

Health related quality of life will be assessed by the Minnesota Living with Heart Failure Questionnaire (MLHFQ) [43] and the EuroQOL (EQ-5D) questionnaire [44] at each scheduled follow-up visit. In addition, clinical improvement will be assessed by a composite score including quality of life (MLHFQ), deaths, and heart failure hospitalisations [45].

Cost-effectiveness will be analyzed by determining the in-trial incremental cost per quality-adjusted life year gained (QALY) in the access arm compared with the control arm. This evaluation will be from a direct health service perspective, covering the major cost drivers of hospitalisation, emergency department visits, and doctor's office visits, based on data from hospital discharge summaries and follow-up visits.

2.7. Ethical conduct
This study will be conducted in compliance with ISO-14155, guided by Good Clinical Practice (GCP) and in accordance with the Declaration of Helsinki and the laws and regulations in the countries in which it is conducted. Written approval from the Institutional Review Board and/or Medical Ethics Committee is required for centre participation in this study. DOT-HF is sponsored by Medtronic Inc. The sponsor will ensure training of all involved study personal as regarding use and interpretation of diagnostic trend data. All devices used in this investigation have a CE mark, are market released and are being used according to licensed indications. Case report form completion and handling will be performed electronically using an internet-based system.

2.8. Alert intervention algorithm
In order to make comparisons between the two management strategies possible, patients who present to study centres after a device alert or in the context of a clinical heart failure decompensation, will be treated according to standardized intervention algorithms (Fig. 3). These algorithms provide detailed recommendations concerning further diagnosis and treatment. In patients allocated to the "access arm" this includes advice for a thorough review of the intrathoracic impedance and Cardiac Compass® trends. Based on the evidence from diagnostic device data and routine clinical evaluation an appropriate treatment intervention will be applied at the clinician's discretion and based on the intervention algorithm.


Figure 03
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  		Fig. 3 Summary of the intervention algorithm and recommendations for the assessment and treatment of patients randomised to the access arm. Further details are provided in the study protocol. A similar intervention algorithm applies for patients in the control arm, however, without any reference to the device-based monitoring data. AT/AF: atrial tachycardia/atrial fibrillation; VT/VF: ventricular tachycardia/ventricular fibrillation; HR: heart rate.

 
Study personnel will receive comprehensive education and training as to the interpretation and practical use of the diagnostic data. It should be emphasised that all device-based diagnostic data are thought to add useful information to routine clinical patient assessment but are not intended to replace it. Apart from considerations related to the device-specific diagnostic information a similar intervention algorithm is suggested for patients allocated to the "control arm".

2.9. Statistical methods and power calculation
The primary endpoint of the study is the occurrence of death or hospitalisation for heart failure. This endpoint will be analyzed on a time-to-first-event basis using the log-rank test stratified by device type. Analysis will include all randomised patients and will use the intention to treat principle. The hazard ratio associated with allocation to the "access arm" relative to control will be estimated, with corresponding 95% confidence interval, by fitting a Cox proportional hazards model containing the treatment group as a categorical factor and stratified by device type (CRT, CRT-D or ICD). Supporting analyses will be carried out adjusting for appropriate prognostic baseline covariates.

Assuming an event rate of 0.2 events per patient per year for the primary endpoint in the control arm, a 20% reduction in this rate in the "access arm", 90% power at the 5% level of significance and study duration of approximately 5 years, we estimate that approximately 2400 patients will have to be randomised and 868 primary endpoints accrued. The study will continue until this target number of primary endpoints has occurred.

All other time-to-first-event analyses will be conducted in a similar fashion to the primary endpoint. Where appropriate, time to event will also be analyzed including repeat events using the conditional analysis method proposed by Prentice, Williams and Peterson [46]. To account for underlying population heterogeneity of risk, this analysis will incorporate adjustment for relevant covariates. The final specification of the covariates to be used in adjusted analyses and other details of the methodologies to be used will be specified in the final study Statistical Analysis Plan.

2.10. Study Committees
The Steering Committee is responsible for developing the study design, the clinical investigational plan, monitoring the implementation of the protocol and for timely publication of the results. The committee includes a statistician independent of the sponsor.

An Endpoint Committee adjudicates all events that could potentially contribute to a study (primary or secondary) endpoint. Endpoint committee members are not aware of the randomisation assignment of the study subjects.

The responsibility of the independent Data Safety Monitoring Board (DSMB) is to ensure the safety of the study subjects. The DSMB will review the interim outcome data as well as the incidence of adverse events in the study and will make recommendations on whether or not to stop the study prematurely. Any recommendation for stopping because of overwhelming evidence of benefit will be based on a Haybittle-Peto type rule requiring P<0.001 in a 2-sided log-rank test of the primary endpoint. There will be a maximum of 4 interim analyses for benefit.

2.11. Timelines
The first patient was enrolled on 27-Mar-2007. At the time of manuscript submission, 120 patients have been enrolled and recruitment is expected to complete 2010. We expect to present the study results in 2012.


   References
Top
 Abstract
 1. Background
 2. Methods
 References
 

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