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Remote telemonitoring for patients with heart failure: might monitoring pulmonary artery pressure become routine? Expert Rev. Cardiovasc. Ther. 12(8), 1025–1033 (2014)
Kate Hutchinson1‡, Pierpaolo Pellicori*1‡, Riet Dierckx1, John GF Cleland2 and Andrew L Clark1 1 Department of Cardiology, Hull York Medical School, Hull and East Yorkshire Medical Research and Teaching Centre, Castle Hill Hospital, Cottingham, Kingston upon Hull, HU16 5JQ, UK 2 National Heart and Lung Institute, Imperial College, London, UK *Author for correspondence: Tel.: +44 148 246 1811 Fax: +44 148 246 1779 [email protected]
Heart failure is one of the most important medical problems facing societies in developed economies and its prevalence is predicted to rise inexorably in the next few decades as longevity increases. Worsening heart failure leading to hospitalization is associated with a poor prognosis and imposes a substantial burden on health care resources and budgets. Interventions that can stabilize patients should reduce the need for hospitalization and improve prognosis. This might be facilitated by frequent self-monitoring of clinical and physiological variables by patients themselves at home. Rising pulmonary artery pressure is an early sign of cardiac decompensation that may be more sensitive than conventional methods of patient assessment and thus allow early adjustment of medical therapy to avoid hospitalizations and improve patient outcomes. Remote monitoring of pulmonary artery pressure is now possible using devices that can be implanted percutaneously. This innovative technology could become a routine part of the management of heart failure in the next few decades. KEYWORDS: heart failure • implant • invasive • pulmonary hypertension • pulmonary pressure • telemonitoring
‡
Authors contributed equally
Heart failure is common, affecting more than 10 million people in Europe and North America alone [1]. It is the most common reason for hospitalization in England and Wales and the USA, causing or contributing to more than 5% of all medical emergency admissions [2]. The incidence of heart failure increases steeply with age and, indeed, might currently be an inevitable consequence of living longer. Improvements in cardiovascular care for myocardial infarction and hypertension may prolong survival more effectively than they prevent heart failure. Several treatments are known to prolong survival after heart failure has occurred. Consequently, as lifespan extends and survival after the onset of cardiovascular disease increases, the prevalence of heart failure will grow inexorably. Breathlessness and peripheral edema due to pulmonary and peripheral congestion are common features of heart failure that often lead to informahealthcare.com
10.1586/14779072.2014.935340
hospitalization. Following an admission for worsening heart failure, there is a 25% chance of either readmission or death within 12 weeks, and mortality increases with the number of admissions [3,4]. The two great challenges in the management of heart failure are first, to control congestion to stabilize symptoms and second, to prevent sudden catastrophic events (such as the onset of sustained arrhythmias or vascular events such as myocardial infarction or stroke), which can cause sudden deterioration or death. Rationale for home telemonitoring of heart failure
Telemonitoring has long been done in hospital wards but recent advances in technology have made remote monitoring in the patient’s home feasible. The taxonomy of telemonitoring is still being developed but includes noninvasive approaches such as structured telephone
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support or home telemonitoring (HTM). More invasive approaches include incorporating monitoring technology into pacemakers and defibrillators and the use of standalone hemodynamic monitoring devices implanted through the percutaneous/transvenous route into the pulmonary artery (PA) or across the interatrial septum. HTM services allow health care professionals to monitor symptoms and physiological variables, such as heart rate and rhythm, blood pressure, weight and now also intracardiac and PA pressures. If problems are identified, patients can be given advice over the telephone, community services can be alerted to make a home visit or the patient can be recalled to the clinic for review. Services are likely to evolve in the future with patients being able to interact with their monitoring information directly, receiving advice on what actions to take based on computerized decision-support algorithms with health care professionals only alerted when matters appear to be getting out of control. HTM offers an alternative to traditional medical management of heart failure by allowing physicians to respond early to changes that may precede clinical deterioration or predict admission to hospital. The aim of HTM is to improve symptoms, reduce hospitalizations and, ultimately, improve outcomes in patients. The current emphasis is shifting from trying to detect deterioration, a strategy that has met with limited success due to the high rate of false compared to true positive alerts, to trying to maintain health, a strategy designed to keep patients’ measurements in their personal ideal range. HTM also allows health care to be more easily accessible and more equitable, particularly in geographically isolated areas [5,6]. Heart failure is a clinical condition suitable for HTM for four important reasons: it is common, it has a poor prognosis, treatment is highly effective but often not optimally deployed and effective treatment requires monitoring of several key variables. Monitoring alone is probably of no benefit but what is done with the information acquired can be. Advancing technology and increasing the availability of monitoring devices are driving the research into HTM for heart failure [5]. Evidence for noninvasive remote monitoring
HTM might reduce hospitalizations and mortality in appropriately selected patients with heart failure. In particular, patients with a history of a recent hospitalization who are not yet optimally treated, seem to benefit [7–9]. The mechanisms responsible for the effect are still unclear but may include better medical advice and management, patient empowerment and adherence to advice and treatment and/or earlier intervention for exacerbations [10–12]. A recent Cochrane meta-analysis including 16 randomized trials suggested that structured telephone support does not reduce mortality [13] but lowers heart failure related hospitalizations; a more recent randomized controlled trial did not confirm the effect on hospitalization [14]. Conflicting results may be due to many factors. Different populations and medical cultures (e.g., Argentina vs USA) have been studied with different 1026
interventions, different methods of data collection and different durations of follow-up [15]. On the other hand, trials of HTM measuring symptoms and physiological variables have, fairly consistently, shown a greater impact on mortality than on hospitalization, especially when targeted at patients with a recent hospitalization for worsening heart failure [7]. It is possible that HTM simply does not reduce hospitalizations. Alternatively, HTM may prevent some admissions but precipitate others that may be lifesaving. Some recent trials have been neutral. This may reflect the inclusion of well-managed, stable patients where HTM is unlikely to improve treatment or outcome [16]. HTM is much more likely to be effective when deployed in a real-world setting where most patients do not usually receive optimal treatment. If there are enough resources to ensure that all patients are closely monitored by conventional means and expertly treated, then noninvasive HTM is unlikely to add much. However, hemodynamic monitoring might add something even to well-resourced expert care for reasons outlined below. Which variables should be measured in telemonitoring programs?
For a HTM program to be successful in reducing or preventing hospitalization, there must first be treatments available that are known to improve outcome. If effective treatments require measurement of symptoms and physiological measurements for optimal delivery, then there is a good chance that HTM will improve outcome. Furthermore, a safe, reliable and robust method of measuring, recording and reporting these changes must be available and acceptable for patients to use in their homes (TABLE 1). An example might be to measure body weight regularly with the thought that fluid retention might cause weight gain and lead to an admission. Early detection of weight gain could prompt a change in diuretic therapy, thereby preventing admission. The WHARF trial [8] involved measurement of daily weight by patients with advanced heart failure and severe symptoms. The trial found no difference in readmission rates between the treatment and control groups (primary outcome), although patients in the HTM arm had a lower mortality. It is unclear whether HTM of weight failed to identify the risk of readmission or if the HTM service failed to deliver intervention in a timely fashion to correct deterioration or if HTM appropriately alerted the service leading to a life-saving admission. In the more recent WISH trial [17], 344 patients recently hospitalized for heart failure were assigned to HTM (automatic transmission of daily weight to the heart failure clinic) or control (asked to contact the heart failure clinic if there is an increase in weight of >2 kg in 3 days). Although patients in the HTM group weighed themselves more often, the investigators found no reduction in readmissions or deaths. There is general agreement that monitoring weight alone lacks both sensitivity and specificity for predicting admissions for heart failure [18]. One consistently powerful prognostic marker in heart failure is the plasma concentration of natriuretic peptides. Serial measurements might be a useful method for detecting worsening Expert Rev. Cardiovasc. Ther. 12(8), (2014)
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Table 1. Potential variables that can be monitored in patients with heart failure: advantages and disadvantages. Potential variables to be monitored
Advantages
Disadvantages
Symptoms
• • • • •
• Insensitive (e.g., sedentary patients may not have breathlessness until they develop pulmonary edema) • Nonspecific (multiple reasons for breathlessness – COPD, obesity) • Need other data to inform treatment decisions
Signs
• Possible target for treatment • Prognostic • Noninvasive
• Requires sensor technology unless patient self-reported
Body weight
• Short-term changes in weight are a guide to fluid balance • Rapid weight gain precedes some heart failure admissions • Noninvasive • Low cost
• Many home weight scales are accurate only to nearest 0.5 kg (a measured 0.5 kg change could be as much as 1.0 kg)
Body composition measured by bioimpedance
• More accurate weights (forces patients to take socks and shoes off!)
• Limited experience in trials
Heart rate (and rhythm) (measured periodically noninvasively)
• Possible target for treatment • Prognostic • Detects AF (not all systems measure rhythm)
• Requires heart rate sensor • Daily variability • Influenced by duration of rest, stress and fever
Heart rate (implanted device)
• 24 h monitoring possible • Arrhythmia detection • Heart rate variability and nocturnal heart rate may be better guide to WHF/prognosis • Devices can also measure patient activity – low activity levels are a sign of WHF
• Requires device implantation
Blood pressure
• Possible target for treatment • Prognostic
• Requires sphygmomanometer • Daily variability • Influenced by underling rhythm, with beatto-beat variability (i.e., AF) • Influenced by duration of rest and stress
Plasma NT-proBNP
• Possible target for treatment • Prognostic • Finger-stick BNP test available
• Requires assay device • Daily fluctuation • Need to detect AF & measure renal function to interpret • Cost of tests
Noninvasive hemodynamics by bioimpedance
• Noninvasive
• Doubts about precision and reproducibility • Large differences between systems – evolving field
Pulmonary congestion by remote dielectric sensing radar technology
• Noninvasive • Potentially more accurate than other measures of lung congestion
• Limited experience
Hemodynamic monitoring using intracardiac leads
• • • •
• • • • •
Target for treatment Prognostic Noninvasive Simple to assess Low cost
Possible target for treatment Prognostic Continuous monitoring Minimal patient effort required (although can enable self-care if patient is willing and able)
Risk of implantation procedure (low) Risk of infection Long-term reliability Need for replacement every 5–10 years Costly
AF: Atrial fibrillation; BNP: B-type natriuretic peptide; WHF: Worsening heart failure.
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Table 1. Potential variables that can be monitored in patients with heart failure: advantages and disadvantages (cont.). Potential variables to be monitored
Advantages
Disadvantages
Hemodynamic monitoring (wireless)
• • • •
• • • •
Possible target for treatment Prognostic Continuous monitoring Minimal patient effort required (although can enable self-care if patient is willing and able)
Risk of implantation procedure (very low) Risk of infection (low) Costly Long-term experience is lacking
AF: Atrial fibrillation; BNP: B-type natriuretic peptide; WHF: Worsening heart failure.
congestion before it becomes clinically overt. Although preliminary results are promising [19–21], plasma concentrations of natriuretic peptide levels are confounded by common comorbidities, such as atrial fibrillation and renal dysfunction, making interpretation complex [22]. Furthermore, it is not clear how often plasma levels should be measured. New devices can provide accurate measurements from a finger-prick sample. The recent HABIT trial [23] enrolled 187 patients who self-monitored B-type natriuretic peptide (BNP) by a finger-stick test, demonstrating feasibility. Further trials are required to show efficacy. Remote monitoring with implanted devices Impedance monitoring devices
Many patients with heart failure have devices implanted for cardiac resynchronization therapy (CRT) and/or defibrillation (implantable cardioverter defibrillators [ICDs]). These devices can monitor the heart rate, heart rate variability and patient activity and provide information on arrhythmias as well as device battery life and function. Some of the devices can also measure intrathoracic impedance, which is a guide to pulmonary congestion [24]. Impedance decreases as intrathoracic fluid accumulates. However, the sensitivity and accuracy of intrathoracic impedance monitoring for predicting hospitalization or worsening heart failure is low, and so far its clinical use has not translated into a better outcome [25,26]. The SENSE-HF trial enrolled 501 patients (90% on diuretics). The intrathoracic fluid monitoring feature (OptiVolÒ) had a very low sensitivity in predicting heart failure deterioration in the first 6 months following implantation [25]. In DOT-HF, 335 patients receiving an ICD or CRT (90% on diuretics) were randomized to having thoracic impedance data available to physicians and patients or not. The trial was stopped early because of an increase in outpatient visits and heart failure hospitalizations due to the alerts [26]. Why monitor hemodynamics?
The concept of HTM as a technique for improving management led to the development of long-term implantable devices to measure hemodynamics more precisely either from the right ventricle (RV), PA or left atrium (LA). However, it is important to realize that using such data to guide management is founded on concepts rather than on evidence. Hemodynamic measurements have not previously been available on a long1028
term daily basis to guide treatment and therefore it has been impossible to gather evidence until recently. Pulmonary hypertension is common in heart failure [27–32]. High LV filling pressure and secondary increases in left atrial pressure are transmitted to the pulmonary circulation leading first to passive pulmonary capillary hypertension and then to active pulmonary arteriolar constriction, each contributing to a rise in PA pressure [30,33,34]. Pulmonary hypertension increases the load on the RV and eventually leads to a rise in RA pressure and the development of peripheral venous congestion. Most patients with chronic heart failure have some degree of biventricular failure and LA and RA pressures tend to correlate [32]. Registries and observational studies have reported that higher PA pressure measured by echo correlates with higher plasma concentrations of natriuretic peptides and worse outcomes for patients with either reduced or preserved LV systolic function [35–37]. Invasive measurements of LA or PA pressure might be a useful method to detect worsening LV function and the response to therapy. Trials of conventional right heart catheterization
The ESCAPE trial (n = 433) compared traditional medical care to management guided by a continuous measurement of PA pressure using a flotation catheter in patients hospitalized with severe heart failure (the catheter was left in place for a median of 1.9 days in the treatment group). The study was neutral for the combined primary endpoint of days alive and out of hospital but 4.2% of patients experienced an adverse event related to their PA catheter [38]. There are several reasons why the results of the trial may have been neutral. All the patients had advanced heart failure, with an average ejection fraction of 19%. The patients may have been too sick to respond. Other groups of patients might have more to gain from tailored therapy, although it would be pure speculation to suggest which these might be. A single reading may be insufficient to guide therapy in the longer term. Continuous monitoring of PA pressure, on the other hand, might allow repeated changes to medication and be more helpful. Trials monitoring right ventricular pressure via an implanted lead
A lead placed in the RV outflow tract can be used to monitor PA pressure either as part of a dedicated hemodynamic Expert Rev. Cardiovasc. Ther. 12(8), (2014)
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Mean age 61 years 27% female 22% had LVEF >40% >90% on diuretics 90% on BB 78% on ACE-I or ARB Pulmonary artery mean pressure 30 mmHg
Specific recommendations were made to utilize invasive readings in HF management by using a defined algorithm in the protocol. A total of 1404 HF medications changes were made. Diuretics were the most common drug changed (68%), followed by ARB or ACE-I (9%) and nitrates (8%) Safety endpoint: • 98.6% freedom from system-related complications • No pressure-sensor failures occurred Efficacy endpoint: • Significant HF-related hospitalizations reduction at 6 months by 28% in the treatment group (37% reduction in HFrelated hospitalization at end entire FU of 15 months in treatment group vs others)
† Trial interrupted because of high failure rate of the implanted hemodynamic lead in other earlier trials. ACE-I: ACE inhibitor; ARB: Angiotensin II receptor blocker; BB: Beta-blockers; COPD: Chronic obstructive pulmonary disease; eGFR: Estimated glomerular filtration rate; FU: Follow-up; HF: Heart failure; ICD: Implantable cardioverter defibrillator; LVEF: Left ventricular ejection fraction; NYHA: New York Heart Association.
• • • • • • •
6 months for primary endpoints (entire FU 15 months)
• NYHA class III (regardless of ejection fraction) • eGFR >25 mL/min/1.73 m2
No protocol recommendations for treatment Lack of uniformity of pressurebased treatment strategies
Safety endpoint: • 91% freedom from system-related complications† Efficacy endpoint: • No reduction of HF-related events (p = 0.98)
CHAMPION (45) – 550
Mean age 55 years 31% female Mean LVEF 23% >90 on diuretics >95% on BB >90% on ACE-I or ARB
No protocol recommendations for treatment Lack of uniformity of pressurebased treatment strategies
12 months (6 months for safety endpoint)
• NYHA class II or III • eGFR >30 mL/min/1.73 m2 • Clinical indication for an ICD
REDUCE-HF (44) – 400 • • • • • •
Safety endpoint: • No pressure-sensor failures • System-related complications: 8% of cases Efficacy endpoint: • Nonsignificant 21% lower rate of all HFrelated events compared with the control group (p=0.33)
6 months
• • • • •
• NYHA class III or IV (regardless of ejection fraction) • HF hospitalization during previous 6 months • No severe COPD, pulmonary arterial hypertension, creatinine >3.5 mg/dl or chronic renal dialysis; implanted ICD
COMPASSHF (42) – 274
Mean age 58 years 35% Female >90% on diuretics >80% on BB >80% on ARB or ACE-I
Primary endpoint
FU length
Patient population
Main inclusion/exclusion criteria
Trial and size
HF medication changes
monitoring system or added to an ICD. PA diastolic pressure can be derived from the RV pressure at the time of the pulmonary valve opening. There is a strong correlation (r = 0.84) between PA pressure estimated in this way and actual PA pressures measured under a variety of conditions (TABLE 2) [39–41]. The CHRONICLE device was a subcutaneously implanted device, with a transvenous lead positioned in the RV outflow tract or the septum. The device continuously measured RV systolic and diastolic pressures, body temperature, physical activity and heart rate and estimated PA diastolic pressures. Patients could upload data from the device remotely, allowing physicians to view the measurements online. Chronicle Offers Management to Patients with Advanced Signs and Symptoms of Heart failure (COMPASS-HF) was a trial involving 274 patients with a broad range of left ventricular ejection fraction (LVEF) and in New York Heart Association (NYHA) class III or IV all of whom had a CHRONICLE device implanted [42]. Patients were randomized, single-blind with their cardiologist receiving or being blind to the monitoring data. Although the safety endpoints (freedom from system-related complications and freedom from pressure-sensor failure) were met, the primary efficacy endpoint (reduction in the rate of heart failure related events at 6 months) was not. Further analysis showed that patients with lower filling pressures had fewer events [43]. The risk of events increased as daily estimated PA diastolic pressure increased; from 20% at 18 mmHg to >50% at 30 mmHg, suggesting that monitoring this variable and adjusting treatment to control it might improve outcome (FIGURE 1). Failure to intervene effectively, largely reflecting the fact that these patients were already on full
Table 2. List of major trials of long-term implantable devices to monitor right-sided hemodynamics.
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56% 34% 20%
Risk at 6 months (%)
Risk of HF events
18 mmHg 25 mmHg
30 mmHg
ePAD-mmHg
Figure 1. Risk of heart failure events according to estimated pulmonary artery diastolic pressure. The risk of events increased significantly with higher daily estimated ePAD, from 20% at 18 mmHg to more than 50% at 30 mmHg. ePAD: Estimated pulmonary artery diastolic pressure. Adapted from [43].
guideline-indicated therapy with few additional therapeutic options, may have accounted for the failure of HTM to improve outcome. REDUCE-hf planned to recruit 1300 patients with a reduced LVEF and in NYHA class II or III who had a clinical indication for an ICD, on guideline-indicated medicines for at least 3 months and had at least one heart failure related event in the preceding 12 months. All patients received a hemodynamic monitoring lead implanted into the RV side of the septum in addition to the ICD lead and uploaded data to a secure server. Clinicians were asked to review the data via an internet connection at least weekly only in patients randomized to the HTM strategy [44]. Only 400 patients were enrolled because of the high failure rate of the implanted hemodynamic lead (4% failure at 4 years). There was no difference between the two groups in the primary combined endpoint of heart failure hospitalizations and emergency department or urgent clinic visits [44]. Patients had fewer events than predicted regardless of the assigned group, perhaps reflecting the high quality of care and pharmacological intervention. However, the study again confirmed that patients with higher PA pressures are at greater risk of experiencing heart failure related events. The complexity, indeed near-impossibility, of conducting blinded trials of HTM may also have contributed to the neutral results. Larger trials with more robust endpoints may be preferable in the presence of blinding. Blinding thwarts one of the potential mechanisms of benefit of HTM: a better informed clinician who can intervene more effectively. Monitoring PA pressure by wireless devices
The CardioMEMS sensor is a wireless device placed in a branch of the left lower lobe PA to measure pressure. CHAMPION was a randomized controlled, patient-blinded trial including 550 patients with a broad range of LVEF and in NYHA class III who had been hospitalized for heart failure in the previous 12 months [45]. All patients were treated with guideline-directed 1030
therapy at the time of device implantation and >90% were taking loop diuretics. Patients were instructed to take daily readings of their PA pressure which were transmitted to a central server and then, in those assigned to PA pressure-guided therapy, to their cardiologist. The mean and systolic PA pressures at baseline were 30 ± 10 mmHg and 45 ± 15 mmHg, respectively. The key things about the trial were that a target range for PA pressure was set and there were instructions on how to modify PA pressure. Thus, the PA pressure and the underlying disease were the targets for therapy rather than symptoms and signs. There was a 28% reduction in the primary endpoint of heart failure related hospitalization in the treatment group compared with the control group at 6 months and a 37% reduction over the mean follow-up of 15 months [45]. There was a greater reduction in mean PA pressure in patients assigned to pressure management. There were more changes in pharmacological therapy in the monitored group (2468 changes, an average of nine per patient) compared to the control group (1061 changes, four per patient), indicating that the intervention group was treated more actively. In particular, there was much greater use of nitrates in the monitored group as well as more intensive use of diuretics, but also more changes in beta-blockers, ACE inhibitors and mineralocorticoid antagonists as well as hydralazine. The number of device-related complications was very low, with the overall freedom from device or system-related complications being 99% across all patients [45]. CHAMPION might be considered the first trial of HTM that has used a health maintenance strategy to keep the patient as close to an ideal range of PA pressure possible, rather than a crisis management strategy, only responding to measurements that are thought to reflect imminent decompensation. Earlier intervention is more likely to alter the trajectory of disease. So far, CHAMPION is the only adequately powered randomized controlled trial of HTM of PA pressure. Several similar devices are in development that are likely to create healthy price competition; currently, the cost of these systems is substantial and can only be justified for use in selected patients at high risk of recurrent or prolonged hospital admissions. Clinician-led versus patient-led care
In several trials of HTM (both noninvasive and invasive), patients in the HTM limb had a far greater number of interactions with health care professionals than those in the control group [7,42,26]. While outcome results from these trials have been promising, frequent review by a health care provider might not be affordable. More focus on technology-supported, patient self-management and less focus on review by physicians could be a solution to building a successful HTM program. A more integrated approach among health care providers, patients and carers needs to be developed. The following trials on LA pressure monitoring are a major step in this direction. Left atrial pressure monitoring
A range of devices are being developed to measure LA pressure. Systems currently in clinical trials require an LA Expert Rev. Cardiovasc. Ther. 12(8), (2014)
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Telemonitoring of PA pressure
pressure-monitoring, transvenous lead attached to a subcutaneous pacemaker-like device. Leadless systems that can be delivered by a percutaneous transvenous catheter are also being developed. HOMEOSTASIS was an observational trial of a pacemakerlike device with an LA pressure-monitoring lead. Twice-daily measurement of LA pressure and a computerized management algorithm, was designed to advise the patient directly, rather than the health professionals monitoring the optimal diuretic dose [46]. Events were less frequent after patients used the monitoring system, compared to the previous 3 months. Daily mean LA pressures fell when patients used the monitoring device [46]. Providing patients with technology that enables selfmanagement could be a game-changer in the evolution of HTM, in terms of efficacy, feasibility and cost. The Left Atrial Pressure Monitoring to Optimize Heart Failure Therapy (LAPTOP-HF) trial is an open-label, randomized, controlled trial that should complete by 2016. This study aims to recruit 730 patients with heart failure with a broad range of LVEF, advanced symptoms and raised NT-proBNP (>1500 ng/l). The intervention is either a stand-alone LA pressure-measuring device, or such a device integrated into a CRT system. Patients in both the actively monitored and control groups will have a handheld patient advisory module which, in the intervention group, will advise on treatment based on hemodynamic data, but in the control group will simply remind patients to take their medications as prescribed. Patients are being followed up for 12 months. The primary outcome of the study is freedom from cardiovascular and neurological events [47]. Conclusion
There is powerful evidence that higher PA pressures are associated with a worse outcome in patients with heart failure and that rising PA pressures predict decompensation and may be a target for treatment. However, further research is needed to confirm that the net benefits of a treatment strategy based on PA pressure justify the extra costs and effort on the part of patients and clinicians. Identifying the right patient, the right time to intervene and new therapies to reduce PA pressure are likely to be key to success. Expert commentary
Heart failure is one of the most important health problems facing already stretched health care systems in the coming decades. Advancing age, increasing comorbidities and a greater variety of effective therapies will make management even more complex. The prognosis of heart failure is reported to be as bad as cancer [48], but just as there are different forms of cancer, there are different heart failure phenotypes leading to different outcomes. Some patients, such as those with low PA pressures, are at low risk and might not benefit from or be harmed by more intensive therapy. Those with very high PA pressures might be at such high risk that no intervention will help. Treatment tailored to the changing needs of the individual patient (personalized care) is likely to be more effective and safer. Many people now envision that this will become the standard approach to manage informahealthcare.com
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long-term medical conditions in the near future. HTM, including appropriate use of implanted systems, is likely to be a requisite enabler of this approach for heart failure. The evidence that high PA pressure is associated with a worse outcome in patients with heart failure is compelling; and the evidence that a rise in PA pressure is common just before an acute admission to hospital is also strong. The evidence that monitoring changes in PA pressure and intervening according to a predefined protocol is beneficial is also growing. However, more evidence that using PA pressure as a therapeutic target improves outcome is required. Patients who take part in clinical trials do better, either because they have a different psychology and perhaps are more likely to be taking their medication, or because they receive more medical and nursing attention and better care, even if they are assigned to the control group or placebo [49]. Accordingly, it is important that HTM technologies are assessed by randomized controlled trials, although cluster-randomized trials may be more appropriate than individual patient randomization. Implantation of an invasive monitoring device is safe in experienced hands and drop-out rates of CHAMPION, REDUCE-hf and COMPASS-HF trials were low [42,44,45]. However, more evidence of benefit is required. If implanted hemodynamic monitoring devices do lead to better outcomes, then they could become a routine part of the management of most patients with heart failure. Five-year view
In 5 years time, we will have data from many more randomized controlled trials of HTM with both noninvasive and implanted technologies that will hopefully demonstrate and quantify benefit. We will have data from cohorts of patients with long-term follow-up that will demonstrate safety or otherwise. We will have many more technologies available for monitoring and improved methods of transmitting data securely. Although patients expect their health records to be treated with respect, data security has been of greater concern to the media (and therefore politicians) than to patients themselves. However, malicious interference with the transmission of data on which treatment decisions are based is a matter of real rather than imaginary concern. In 5 years, HTM programs and conventional care services may also be better integrated. Necessarily, the trials of invasive monitoring conducted to date have focused on those patients with well-defined, usually single, pathologies who are at high risk of events. The extent to which complex (and expensive) monitoring equipment might be beneficial to patients who are more typically encountered – the elderly and those with multiple comorbidities that cause many readmissions – is uncertain and unlikely to be directly tested. Chronic disease management programs may opt for lowtechnology solutions where patients’ general health and wellbeing can be assessed readily: answers to questions such as ‘how are you feeling?’, together with data on pulse, blood pressure and heart rhythm, might be more helpful in managing an older patient with several coincident chronic conditions than 1031
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measuring PA pressure. From this perspective, invasive HTM may have a limited role. However, it may be precisely the older, multimorbid patient that has most to gain from more sophisticated technology that allows treatment to be targeted better at their specific pathophysiology when symptoms become a nearuseless guide to treatment (e.g., the older immobile patients with heart failure and chronic obstructive pulmonary disease whose first warning of decompensation is the development of pulmonary edema).
Financial & competing interests disclosure
JGF Cleland has received research support for telemonitoring from Philips and honoraria for speaking and advice from St Jude Medical. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues • Heart failure is common and prognosis is often poor. It is a major health care burden. • Many effective treatments exist but they are often poorly deployed. • Home telemonitoring could improve the delivery of care. • Hemodynamic monitoring may help optimize therapy; treating the underlying disease rather than symptoms and signs is more likely to alter the natural history of the disease favorably. • Trials investigating therapy guided by invasive hemodynamic monitoring have shown promising results. • Identifying the right patient, the right time to intervene and new therapies to improve hemodynamics are all likely to be the key to the success of a hemodynamic home telemonitoring strategy.
Management System (TEN-HMS) study. J Am Coll Cardiol 2005;45(10):1655-44
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Goldberg L, Piette J, Walsh M, et al. Randomised trial of a daily electronic homemonitoring system in patients with advanced heart failure (WHARF) trial. Am Heart J 2003;146(4):705-12 Dendale P, De Keulenaer G, Troisfontaines P, et al. Effect of a telemonitoring-facilitated collaboration between general practitioner and heart failure clinic on mortality and rehospitalization rates in severe heart failure: the TEMA-HF 1 (Telemonitoring in the Management of Heart Failure) study. Eur J Heart Fail 2012;14(3):333-40 Piette J, Gregor M, Share D, et al. Improving heart failure self-management support by actively engaging out-of-home caregivers: results of a feasibility study. Congest Heart Fail 2008;14:12-18
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Mortara A, Pinna G, Maestri R, et al. Home telemonitoring in heart failure patients: the HHH study (Home or Hospital in Heart Failure). Eur J Heart Fail 2009;11:312-18
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Capomolla S, Pinna G, Maestri R, et al. The telemonitoring service [Il servicio di teleminitoraggoio]. Monaldi Arch Chest Dis 2005;64(2):135-6
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Inglis S, Clark R, McAlister F, et al. Structured telephone support or telemonitoring programmes for patients with chronic heart failure. Cochrane Database Syst Rev 2011;4(8):1-144
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Chaudhry S, Mattera J, Curtis J, et al. Telemonitoring in patients with heart failure. N Engl J Med 2010;363(24):2301-9
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GESICA Investigators. Randomised trial of telephone intervention in chronic heart failure: DIAL trial. Br Med J 2005;331:425
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Koehler F, Winkler S, Schieber M, et al. Impact of remote telemedical management on mortality and hospitalizations in ambulatory patients with chronic heart failure: the telemedical interventional monitoring in heart failure study. Circulation 2011;123(17):1873-80
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Lynga P, Persson H, Haag-Martinell E, et al. Weight monitoring in patients with severe heart failure (WISH). A randomized controlled trial. Eur J Heart Fail 2012; 14(4):438-44
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Zhang J, Goode K, Cuddihy P. Predicting hospitalization due to worsening heart failure using daily weight measurement: analysis of the Trans-European Network-Home-Care Management (TENHMS) study. Eur J Heart Fail 2009;11: 420-7
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De Vecchis R, Esposito C, Di Biase G, et al. B-type natriuretic peptide-guided versus symptom-guided therapy in outpatients with chronic heart failure: a systematic review with meta-analysis. J Cardiovasc Med 2014;15(2):122-34
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Troughton R, Michael Felker G, Januzzi J. Natriuretic peptide-guided heart failure management. Eur Heart J 2013;35(1): 16-24
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van Veldhuisen D, Braunschweig F, Conraads V, et al. Intrathoracic impedance monitoring, audible patient alerts, and outcome in patients with heart failure. Circulation 2011;124:1719-26
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Hoeper M, Bogaard H, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol 2013; 62(25):D42-50
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Lam C, Borlaug B, Kane G, et al. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study. J Am Coll Cardiol 2009;53:1119-26
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Leung C, Moondra V, Catherwood E, Andrus B. Prevalence and risk factors of pulmonary hypertension in patients with elevated pulmonary venous pressure and preserved ejection fraction. Am J Cardiol 2010;106:284-6
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Vachiery J, Adir Y, Barbera J, et al. Pulmonary hypertension due to left heart diseases. J Am Coll Cardiol 2013;62(25): D100-8
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Pellicori P, Kallvikbacka-Bennett A, Zhang J, et al. Revisiting a classical clinical sign: jugular venous ultrasound. Int J Cardiol 2014;170(3):364-70 Drazner M, Hamilton M. Relationship between right and left-sided filling pressures in 1000 patients with advanced heart failure. J Heart Lung Transplant 1999; 18(11):1126-32 Moraes D, Colucci W, Givertz M. Secondary pulmonary hypertension in chronic heart failure: the role of the endothelium in pathophysiology and management. J Am Coll Cardiol 2000;102: 1718-23 McGoon M, Benza R, Escribano-Subias P, et al. Pulmonary arterial hypertension: epidemiology and registries. J Am Coll Cardiol 2013;62(25):D51-9
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Bourge R, Abraham W, Adamson P, et al. Randomised controlled trial of an implantable continuous hemodynamic monitor in patients with advanced heart failure. J Am Coll Cardiol 2008;51(11): 1073-9
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Stevenson L, Zile M, Bennett T, et al. Chronic ambulatory intracardiac pressures and future heart failure events. Circ Heart Fail 2010;3(5):580-7
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Adamson P, Gold M, Bennett T, et al. Continuous hemodynamic monitoring in patients with mild to moderate heart failure: results of the reducing decompensation events utilizing intracardiac pressures in patients with chronic heart failure (REDUCEhf) trial. Congest Heart Fail 2011;17:248-54
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Pellicori P, Carubelli V, Zhang J. IVC diameter in patients with chronic heart failure: relationships and prognostic significance. JACC Cardiovasc Imaging 2013;6:16-28
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Damy T, Goode K, Kallvikbacka-Bennett A. Determinants and prognostic value of pulmonary arterial pressure in patients with chronic heart failure. Eur Heart J 2010;31: 2280-90
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Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonary artery hemodynamic monitoring in chronic heart failure: a randomized controlled trial. Lancet 2011;377:658-66
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Bursi F, McNallan S, Redfield M. Pulmonary pressures and death in heart failure: a community study. J Am Coll Cardiol 2012;17:222-31
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Ritzema J, Troughton R, Melton I, et al. Physician-directed patient self-management of left atrial pressure in advanced heart failure. Circulation 2014;121:1086-95
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Clinical trials number: NCT01121107. Left atrial pressure monitoring to optimize heart failure therapy (LAPTOP-HF). Available from: http://clinicaltrials.gov/show/ NCT01121107
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Magalski A, Adamson P, Gadler F, et al. Continuous ambulatory right heart pressure measurements with an implantable hemodynamic monitor: a multicenter, 12-month follow-up study of patients with chronic heart failure. J Card Fail 2002;8(2): 63-70
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Remote telemonitoring for patients with heart failure: might monitoring pulmonary artery pressure become routine? Expert Rev. Cardiovasc. Ther. 12(8), 1025–1033 (2014)
Kate Hutchinson1‡, Pierpaolo Pellicori*1‡, Riet Dierckx1, John GF Cleland2 and Andrew L Clark1 1 Department of Cardiology, Hull York Medical School, Hull and East Yorkshire Medical Research and Teaching Centre, Castle Hill Hospital, Cottingham, Kingston upon Hull, HU16 5JQ, UK 2 National Heart and Lung Institute, Imperial College, London, UK *Author for correspondence: Tel.: +44 148 246 1811 Fax: +44 148 246 1779 [email protected]
Heart failure is one of the most important medical problems facing societies in developed economies and its prevalence is predicted to rise inexorably in the next few decades as longevity increases. Worsening heart failure leading to hospitalization is associated with a poor prognosis and imposes a substantial burden on health care resources and budgets. Interventions that can stabilize patients should reduce the need for hospitalization and improve prognosis. This might be facilitated by frequent self-monitoring of clinical and physiological variables by patients themselves at home. Rising pulmonary artery pressure is an early sign of cardiac decompensation that may be more sensitive than conventional methods of patient assessment and thus allow early adjustment of medical therapy to avoid hospitalizations and improve patient outcomes. Remote monitoring of pulmonary artery pressure is now possible using devices that can be implanted percutaneously. This innovative technology could become a routine part of the management of heart failure in the next few decades. KEYWORDS: heart failure • implant • invasive • pulmonary hypertension • pulmonary pressure • telemonitoring
‡
Authors contributed equally
Heart failure is common, affecting more than 10 million people in Europe and North America alone [1]. It is the most common reason for hospitalization in England and Wales and the USA, causing or contributing to more than 5% of all medical emergency admissions [2]. The incidence of heart failure increases steeply with age and, indeed, might currently be an inevitable consequence of living longer. Improvements in cardiovascular care for myocardial infarction and hypertension may prolong survival more effectively than they prevent heart failure. Several treatments are known to prolong survival after heart failure has occurred. Consequently, as lifespan extends and survival after the onset of cardiovascular disease increases, the prevalence of heart failure will grow inexorably. Breathlessness and peripheral edema due to pulmonary and peripheral congestion are common features of heart failure that often lead to informahealthcare.com
10.1586/14779072.2014.935340
hospitalization. Following an admission for worsening heart failure, there is a 25% chance of either readmission or death within 12 weeks, and mortality increases with the number of admissions [3,4]. The two great challenges in the management of heart failure are first, to control congestion to stabilize symptoms and second, to prevent sudden catastrophic events (such as the onset of sustained arrhythmias or vascular events such as myocardial infarction or stroke), which can cause sudden deterioration or death. Rationale for home telemonitoring of heart failure
Telemonitoring has long been done in hospital wards but recent advances in technology have made remote monitoring in the patient’s home feasible. The taxonomy of telemonitoring is still being developed but includes noninvasive approaches such as structured telephone
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support or home telemonitoring (HTM). More invasive approaches include incorporating monitoring technology into pacemakers and defibrillators and the use of standalone hemodynamic monitoring devices implanted through the percutaneous/transvenous route into the pulmonary artery (PA) or across the interatrial septum. HTM services allow health care professionals to monitor symptoms and physiological variables, such as heart rate and rhythm, blood pressure, weight and now also intracardiac and PA pressures. If problems are identified, patients can be given advice over the telephone, community services can be alerted to make a home visit or the patient can be recalled to the clinic for review. Services are likely to evolve in the future with patients being able to interact with their monitoring information directly, receiving advice on what actions to take based on computerized decision-support algorithms with health care professionals only alerted when matters appear to be getting out of control. HTM offers an alternative to traditional medical management of heart failure by allowing physicians to respond early to changes that may precede clinical deterioration or predict admission to hospital. The aim of HTM is to improve symptoms, reduce hospitalizations and, ultimately, improve outcomes in patients. The current emphasis is shifting from trying to detect deterioration, a strategy that has met with limited success due to the high rate of false compared to true positive alerts, to trying to maintain health, a strategy designed to keep patients’ measurements in their personal ideal range. HTM also allows health care to be more easily accessible and more equitable, particularly in geographically isolated areas [5,6]. Heart failure is a clinical condition suitable for HTM for four important reasons: it is common, it has a poor prognosis, treatment is highly effective but often not optimally deployed and effective treatment requires monitoring of several key variables. Monitoring alone is probably of no benefit but what is done with the information acquired can be. Advancing technology and increasing the availability of monitoring devices are driving the research into HTM for heart failure [5]. Evidence for noninvasive remote monitoring
HTM might reduce hospitalizations and mortality in appropriately selected patients with heart failure. In particular, patients with a history of a recent hospitalization who are not yet optimally treated, seem to benefit [7–9]. The mechanisms responsible for the effect are still unclear but may include better medical advice and management, patient empowerment and adherence to advice and treatment and/or earlier intervention for exacerbations [10–12]. A recent Cochrane meta-analysis including 16 randomized trials suggested that structured telephone support does not reduce mortality [13] but lowers heart failure related hospitalizations; a more recent randomized controlled trial did not confirm the effect on hospitalization [14]. Conflicting results may be due to many factors. Different populations and medical cultures (e.g., Argentina vs USA) have been studied with different 1026
interventions, different methods of data collection and different durations of follow-up [15]. On the other hand, trials of HTM measuring symptoms and physiological variables have, fairly consistently, shown a greater impact on mortality than on hospitalization, especially when targeted at patients with a recent hospitalization for worsening heart failure [7]. It is possible that HTM simply does not reduce hospitalizations. Alternatively, HTM may prevent some admissions but precipitate others that may be lifesaving. Some recent trials have been neutral. This may reflect the inclusion of well-managed, stable patients where HTM is unlikely to improve treatment or outcome [16]. HTM is much more likely to be effective when deployed in a real-world setting where most patients do not usually receive optimal treatment. If there are enough resources to ensure that all patients are closely monitored by conventional means and expertly treated, then noninvasive HTM is unlikely to add much. However, hemodynamic monitoring might add something even to well-resourced expert care for reasons outlined below. Which variables should be measured in telemonitoring programs?
For a HTM program to be successful in reducing or preventing hospitalization, there must first be treatments available that are known to improve outcome. If effective treatments require measurement of symptoms and physiological measurements for optimal delivery, then there is a good chance that HTM will improve outcome. Furthermore, a safe, reliable and robust method of measuring, recording and reporting these changes must be available and acceptable for patients to use in their homes (TABLE 1). An example might be to measure body weight regularly with the thought that fluid retention might cause weight gain and lead to an admission. Early detection of weight gain could prompt a change in diuretic therapy, thereby preventing admission. The WHARF trial [8] involved measurement of daily weight by patients with advanced heart failure and severe symptoms. The trial found no difference in readmission rates between the treatment and control groups (primary outcome), although patients in the HTM arm had a lower mortality. It is unclear whether HTM of weight failed to identify the risk of readmission or if the HTM service failed to deliver intervention in a timely fashion to correct deterioration or if HTM appropriately alerted the service leading to a life-saving admission. In the more recent WISH trial [17], 344 patients recently hospitalized for heart failure were assigned to HTM (automatic transmission of daily weight to the heart failure clinic) or control (asked to contact the heart failure clinic if there is an increase in weight of >2 kg in 3 days). Although patients in the HTM group weighed themselves more often, the investigators found no reduction in readmissions or deaths. There is general agreement that monitoring weight alone lacks both sensitivity and specificity for predicting admissions for heart failure [18]. One consistently powerful prognostic marker in heart failure is the plasma concentration of natriuretic peptides. Serial measurements might be a useful method for detecting worsening Expert Rev. Cardiovasc. Ther. 12(8), (2014)
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Table 1. Potential variables that can be monitored in patients with heart failure: advantages and disadvantages. Potential variables to be monitored
Advantages
Disadvantages
Symptoms
• • • • •
• Insensitive (e.g., sedentary patients may not have breathlessness until they develop pulmonary edema) • Nonspecific (multiple reasons for breathlessness – COPD, obesity) • Need other data to inform treatment decisions
Signs
• Possible target for treatment • Prognostic • Noninvasive
• Requires sensor technology unless patient self-reported
Body weight
• Short-term changes in weight are a guide to fluid balance • Rapid weight gain precedes some heart failure admissions • Noninvasive • Low cost
• Many home weight scales are accurate only to nearest 0.5 kg (a measured 0.5 kg change could be as much as 1.0 kg)
Body composition measured by bioimpedance
• More accurate weights (forces patients to take socks and shoes off!)
• Limited experience in trials
Heart rate (and rhythm) (measured periodically noninvasively)
• Possible target for treatment • Prognostic • Detects AF (not all systems measure rhythm)
• Requires heart rate sensor • Daily variability • Influenced by duration of rest, stress and fever
Heart rate (implanted device)
• 24 h monitoring possible • Arrhythmia detection • Heart rate variability and nocturnal heart rate may be better guide to WHF/prognosis • Devices can also measure patient activity – low activity levels are a sign of WHF
• Requires device implantation
Blood pressure
• Possible target for treatment • Prognostic
• Requires sphygmomanometer • Daily variability • Influenced by underling rhythm, with beatto-beat variability (i.e., AF) • Influenced by duration of rest and stress
Plasma NT-proBNP
• Possible target for treatment • Prognostic • Finger-stick BNP test available
• Requires assay device • Daily fluctuation • Need to detect AF & measure renal function to interpret • Cost of tests
Noninvasive hemodynamics by bioimpedance
• Noninvasive
• Doubts about precision and reproducibility • Large differences between systems – evolving field
Pulmonary congestion by remote dielectric sensing radar technology
• Noninvasive • Potentially more accurate than other measures of lung congestion
• Limited experience
Hemodynamic monitoring using intracardiac leads
• • • •
• • • • •
Target for treatment Prognostic Noninvasive Simple to assess Low cost
Possible target for treatment Prognostic Continuous monitoring Minimal patient effort required (although can enable self-care if patient is willing and able)
Risk of implantation procedure (low) Risk of infection Long-term reliability Need for replacement every 5–10 years Costly
AF: Atrial fibrillation; BNP: B-type natriuretic peptide; WHF: Worsening heart failure.
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Table 1. Potential variables that can be monitored in patients with heart failure: advantages and disadvantages (cont.). Potential variables to be monitored
Advantages
Disadvantages
Hemodynamic monitoring (wireless)
• • • •
• • • •
Possible target for treatment Prognostic Continuous monitoring Minimal patient effort required (although can enable self-care if patient is willing and able)
Risk of implantation procedure (very low) Risk of infection (low) Costly Long-term experience is lacking
AF: Atrial fibrillation; BNP: B-type natriuretic peptide; WHF: Worsening heart failure.
congestion before it becomes clinically overt. Although preliminary results are promising [19–21], plasma concentrations of natriuretic peptide levels are confounded by common comorbidities, such as atrial fibrillation and renal dysfunction, making interpretation complex [22]. Furthermore, it is not clear how often plasma levels should be measured. New devices can provide accurate measurements from a finger-prick sample. The recent HABIT trial [23] enrolled 187 patients who self-monitored B-type natriuretic peptide (BNP) by a finger-stick test, demonstrating feasibility. Further trials are required to show efficacy. Remote monitoring with implanted devices Impedance monitoring devices
Many patients with heart failure have devices implanted for cardiac resynchronization therapy (CRT) and/or defibrillation (implantable cardioverter defibrillators [ICDs]). These devices can monitor the heart rate, heart rate variability and patient activity and provide information on arrhythmias as well as device battery life and function. Some of the devices can also measure intrathoracic impedance, which is a guide to pulmonary congestion [24]. Impedance decreases as intrathoracic fluid accumulates. However, the sensitivity and accuracy of intrathoracic impedance monitoring for predicting hospitalization or worsening heart failure is low, and so far its clinical use has not translated into a better outcome [25,26]. The SENSE-HF trial enrolled 501 patients (90% on diuretics). The intrathoracic fluid monitoring feature (OptiVolÒ) had a very low sensitivity in predicting heart failure deterioration in the first 6 months following implantation [25]. In DOT-HF, 335 patients receiving an ICD or CRT (90% on diuretics) were randomized to having thoracic impedance data available to physicians and patients or not. The trial was stopped early because of an increase in outpatient visits and heart failure hospitalizations due to the alerts [26]. Why monitor hemodynamics?
The concept of HTM as a technique for improving management led to the development of long-term implantable devices to measure hemodynamics more precisely either from the right ventricle (RV), PA or left atrium (LA). However, it is important to realize that using such data to guide management is founded on concepts rather than on evidence. Hemodynamic measurements have not previously been available on a long1028
term daily basis to guide treatment and therefore it has been impossible to gather evidence until recently. Pulmonary hypertension is common in heart failure [27–32]. High LV filling pressure and secondary increases in left atrial pressure are transmitted to the pulmonary circulation leading first to passive pulmonary capillary hypertension and then to active pulmonary arteriolar constriction, each contributing to a rise in PA pressure [30,33,34]. Pulmonary hypertension increases the load on the RV and eventually leads to a rise in RA pressure and the development of peripheral venous congestion. Most patients with chronic heart failure have some degree of biventricular failure and LA and RA pressures tend to correlate [32]. Registries and observational studies have reported that higher PA pressure measured by echo correlates with higher plasma concentrations of natriuretic peptides and worse outcomes for patients with either reduced or preserved LV systolic function [35–37]. Invasive measurements of LA or PA pressure might be a useful method to detect worsening LV function and the response to therapy. Trials of conventional right heart catheterization
The ESCAPE trial (n = 433) compared traditional medical care to management guided by a continuous measurement of PA pressure using a flotation catheter in patients hospitalized with severe heart failure (the catheter was left in place for a median of 1.9 days in the treatment group). The study was neutral for the combined primary endpoint of days alive and out of hospital but 4.2% of patients experienced an adverse event related to their PA catheter [38]. There are several reasons why the results of the trial may have been neutral. All the patients had advanced heart failure, with an average ejection fraction of 19%. The patients may have been too sick to respond. Other groups of patients might have more to gain from tailored therapy, although it would be pure speculation to suggest which these might be. A single reading may be insufficient to guide therapy in the longer term. Continuous monitoring of PA pressure, on the other hand, might allow repeated changes to medication and be more helpful. Trials monitoring right ventricular pressure via an implanted lead
A lead placed in the RV outflow tract can be used to monitor PA pressure either as part of a dedicated hemodynamic Expert Rev. Cardiovasc. Ther. 12(8), (2014)
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Mean age 61 years 27% female 22% had LVEF >40% >90% on diuretics 90% on BB 78% on ACE-I or ARB Pulmonary artery mean pressure 30 mmHg
Specific recommendations were made to utilize invasive readings in HF management by using a defined algorithm in the protocol. A total of 1404 HF medications changes were made. Diuretics were the most common drug changed (68%), followed by ARB or ACE-I (9%) and nitrates (8%) Safety endpoint: • 98.6% freedom from system-related complications • No pressure-sensor failures occurred Efficacy endpoint: • Significant HF-related hospitalizations reduction at 6 months by 28% in the treatment group (37% reduction in HFrelated hospitalization at end entire FU of 15 months in treatment group vs others)
† Trial interrupted because of high failure rate of the implanted hemodynamic lead in other earlier trials. ACE-I: ACE inhibitor; ARB: Angiotensin II receptor blocker; BB: Beta-blockers; COPD: Chronic obstructive pulmonary disease; eGFR: Estimated glomerular filtration rate; FU: Follow-up; HF: Heart failure; ICD: Implantable cardioverter defibrillator; LVEF: Left ventricular ejection fraction; NYHA: New York Heart Association.
• • • • • • •
6 months for primary endpoints (entire FU 15 months)
• NYHA class III (regardless of ejection fraction) • eGFR >25 mL/min/1.73 m2
No protocol recommendations for treatment Lack of uniformity of pressurebased treatment strategies
Safety endpoint: • 91% freedom from system-related complications† Efficacy endpoint: • No reduction of HF-related events (p = 0.98)
CHAMPION (45) – 550
Mean age 55 years 31% female Mean LVEF 23% >90 on diuretics >95% on BB >90% on ACE-I or ARB
No protocol recommendations for treatment Lack of uniformity of pressurebased treatment strategies
12 months (6 months for safety endpoint)
• NYHA class II or III • eGFR >30 mL/min/1.73 m2 • Clinical indication for an ICD
REDUCE-HF (44) – 400 • • • • • •
Safety endpoint: • No pressure-sensor failures • System-related complications: 8% of cases Efficacy endpoint: • Nonsignificant 21% lower rate of all HFrelated events compared with the control group (p=0.33)
6 months
• • • • •
• NYHA class III or IV (regardless of ejection fraction) • HF hospitalization during previous 6 months • No severe COPD, pulmonary arterial hypertension, creatinine >3.5 mg/dl or chronic renal dialysis; implanted ICD
COMPASSHF (42) – 274
Mean age 58 years 35% Female >90% on diuretics >80% on BB >80% on ARB or ACE-I
Primary endpoint
FU length
Patient population
Main inclusion/exclusion criteria
Trial and size
HF medication changes
monitoring system or added to an ICD. PA diastolic pressure can be derived from the RV pressure at the time of the pulmonary valve opening. There is a strong correlation (r = 0.84) between PA pressure estimated in this way and actual PA pressures measured under a variety of conditions (TABLE 2) [39–41]. The CHRONICLE device was a subcutaneously implanted device, with a transvenous lead positioned in the RV outflow tract or the septum. The device continuously measured RV systolic and diastolic pressures, body temperature, physical activity and heart rate and estimated PA diastolic pressures. Patients could upload data from the device remotely, allowing physicians to view the measurements online. Chronicle Offers Management to Patients with Advanced Signs and Symptoms of Heart failure (COMPASS-HF) was a trial involving 274 patients with a broad range of left ventricular ejection fraction (LVEF) and in New York Heart Association (NYHA) class III or IV all of whom had a CHRONICLE device implanted [42]. Patients were randomized, single-blind with their cardiologist receiving or being blind to the monitoring data. Although the safety endpoints (freedom from system-related complications and freedom from pressure-sensor failure) were met, the primary efficacy endpoint (reduction in the rate of heart failure related events at 6 months) was not. Further analysis showed that patients with lower filling pressures had fewer events [43]. The risk of events increased as daily estimated PA diastolic pressure increased; from 20% at 18 mmHg to >50% at 30 mmHg, suggesting that monitoring this variable and adjusting treatment to control it might improve outcome (FIGURE 1). Failure to intervene effectively, largely reflecting the fact that these patients were already on full
Table 2. List of major trials of long-term implantable devices to monitor right-sided hemodynamics.
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56% 34% 20%
Risk at 6 months (%)
Risk of HF events
18 mmHg 25 mmHg
30 mmHg
ePAD-mmHg
Figure 1. Risk of heart failure events according to estimated pulmonary artery diastolic pressure. The risk of events increased significantly with higher daily estimated ePAD, from 20% at 18 mmHg to more than 50% at 30 mmHg. ePAD: Estimated pulmonary artery diastolic pressure. Adapted from [43].
guideline-indicated therapy with few additional therapeutic options, may have accounted for the failure of HTM to improve outcome. REDUCE-hf planned to recruit 1300 patients with a reduced LVEF and in NYHA class II or III who had a clinical indication for an ICD, on guideline-indicated medicines for at least 3 months and had at least one heart failure related event in the preceding 12 months. All patients received a hemodynamic monitoring lead implanted into the RV side of the septum in addition to the ICD lead and uploaded data to a secure server. Clinicians were asked to review the data via an internet connection at least weekly only in patients randomized to the HTM strategy [44]. Only 400 patients were enrolled because of the high failure rate of the implanted hemodynamic lead (4% failure at 4 years). There was no difference between the two groups in the primary combined endpoint of heart failure hospitalizations and emergency department or urgent clinic visits [44]. Patients had fewer events than predicted regardless of the assigned group, perhaps reflecting the high quality of care and pharmacological intervention. However, the study again confirmed that patients with higher PA pressures are at greater risk of experiencing heart failure related events. The complexity, indeed near-impossibility, of conducting blinded trials of HTM may also have contributed to the neutral results. Larger trials with more robust endpoints may be preferable in the presence of blinding. Blinding thwarts one of the potential mechanisms of benefit of HTM: a better informed clinician who can intervene more effectively. Monitoring PA pressure by wireless devices
The CardioMEMS sensor is a wireless device placed in a branch of the left lower lobe PA to measure pressure. CHAMPION was a randomized controlled, patient-blinded trial including 550 patients with a broad range of LVEF and in NYHA class III who had been hospitalized for heart failure in the previous 12 months [45]. All patients were treated with guideline-directed 1030
therapy at the time of device implantation and >90% were taking loop diuretics. Patients were instructed to take daily readings of their PA pressure which were transmitted to a central server and then, in those assigned to PA pressure-guided therapy, to their cardiologist. The mean and systolic PA pressures at baseline were 30 ± 10 mmHg and 45 ± 15 mmHg, respectively. The key things about the trial were that a target range for PA pressure was set and there were instructions on how to modify PA pressure. Thus, the PA pressure and the underlying disease were the targets for therapy rather than symptoms and signs. There was a 28% reduction in the primary endpoint of heart failure related hospitalization in the treatment group compared with the control group at 6 months and a 37% reduction over the mean follow-up of 15 months [45]. There was a greater reduction in mean PA pressure in patients assigned to pressure management. There were more changes in pharmacological therapy in the monitored group (2468 changes, an average of nine per patient) compared to the control group (1061 changes, four per patient), indicating that the intervention group was treated more actively. In particular, there was much greater use of nitrates in the monitored group as well as more intensive use of diuretics, but also more changes in beta-blockers, ACE inhibitors and mineralocorticoid antagonists as well as hydralazine. The number of device-related complications was very low, with the overall freedom from device or system-related complications being 99% across all patients [45]. CHAMPION might be considered the first trial of HTM that has used a health maintenance strategy to keep the patient as close to an ideal range of PA pressure possible, rather than a crisis management strategy, only responding to measurements that are thought to reflect imminent decompensation. Earlier intervention is more likely to alter the trajectory of disease. So far, CHAMPION is the only adequately powered randomized controlled trial of HTM of PA pressure. Several similar devices are in development that are likely to create healthy price competition; currently, the cost of these systems is substantial and can only be justified for use in selected patients at high risk of recurrent or prolonged hospital admissions. Clinician-led versus patient-led care
In several trials of HTM (both noninvasive and invasive), patients in the HTM limb had a far greater number of interactions with health care professionals than those in the control group [7,42,26]. While outcome results from these trials have been promising, frequent review by a health care provider might not be affordable. More focus on technology-supported, patient self-management and less focus on review by physicians could be a solution to building a successful HTM program. A more integrated approach among health care providers, patients and carers needs to be developed. The following trials on LA pressure monitoring are a major step in this direction. Left atrial pressure monitoring
A range of devices are being developed to measure LA pressure. Systems currently in clinical trials require an LA Expert Rev. Cardiovasc. Ther. 12(8), (2014)
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Telemonitoring of PA pressure
pressure-monitoring, transvenous lead attached to a subcutaneous pacemaker-like device. Leadless systems that can be delivered by a percutaneous transvenous catheter are also being developed. HOMEOSTASIS was an observational trial of a pacemakerlike device with an LA pressure-monitoring lead. Twice-daily measurement of LA pressure and a computerized management algorithm, was designed to advise the patient directly, rather than the health professionals monitoring the optimal diuretic dose [46]. Events were less frequent after patients used the monitoring system, compared to the previous 3 months. Daily mean LA pressures fell when patients used the monitoring device [46]. Providing patients with technology that enables selfmanagement could be a game-changer in the evolution of HTM, in terms of efficacy, feasibility and cost. The Left Atrial Pressure Monitoring to Optimize Heart Failure Therapy (LAPTOP-HF) trial is an open-label, randomized, controlled trial that should complete by 2016. This study aims to recruit 730 patients with heart failure with a broad range of LVEF, advanced symptoms and raised NT-proBNP (>1500 ng/l). The intervention is either a stand-alone LA pressure-measuring device, or such a device integrated into a CRT system. Patients in both the actively monitored and control groups will have a handheld patient advisory module which, in the intervention group, will advise on treatment based on hemodynamic data, but in the control group will simply remind patients to take their medications as prescribed. Patients are being followed up for 12 months. The primary outcome of the study is freedom from cardiovascular and neurological events [47]. Conclusion
There is powerful evidence that higher PA pressures are associated with a worse outcome in patients with heart failure and that rising PA pressures predict decompensation and may be a target for treatment. However, further research is needed to confirm that the net benefits of a treatment strategy based on PA pressure justify the extra costs and effort on the part of patients and clinicians. Identifying the right patient, the right time to intervene and new therapies to reduce PA pressure are likely to be key to success. Expert commentary
Heart failure is one of the most important health problems facing already stretched health care systems in the coming decades. Advancing age, increasing comorbidities and a greater variety of effective therapies will make management even more complex. The prognosis of heart failure is reported to be as bad as cancer [48], but just as there are different forms of cancer, there are different heart failure phenotypes leading to different outcomes. Some patients, such as those with low PA pressures, are at low risk and might not benefit from or be harmed by more intensive therapy. Those with very high PA pressures might be at such high risk that no intervention will help. Treatment tailored to the changing needs of the individual patient (personalized care) is likely to be more effective and safer. Many people now envision that this will become the standard approach to manage informahealthcare.com
Review
long-term medical conditions in the near future. HTM, including appropriate use of implanted systems, is likely to be a requisite enabler of this approach for heart failure. The evidence that high PA pressure is associated with a worse outcome in patients with heart failure is compelling; and the evidence that a rise in PA pressure is common just before an acute admission to hospital is also strong. The evidence that monitoring changes in PA pressure and intervening according to a predefined protocol is beneficial is also growing. However, more evidence that using PA pressure as a therapeutic target improves outcome is required. Patients who take part in clinical trials do better, either because they have a different psychology and perhaps are more likely to be taking their medication, or because they receive more medical and nursing attention and better care, even if they are assigned to the control group or placebo [49]. Accordingly, it is important that HTM technologies are assessed by randomized controlled trials, although cluster-randomized trials may be more appropriate than individual patient randomization. Implantation of an invasive monitoring device is safe in experienced hands and drop-out rates of CHAMPION, REDUCE-hf and COMPASS-HF trials were low [42,44,45]. However, more evidence of benefit is required. If implanted hemodynamic monitoring devices do lead to better outcomes, then they could become a routine part of the management of most patients with heart failure. Five-year view
In 5 years time, we will have data from many more randomized controlled trials of HTM with both noninvasive and implanted technologies that will hopefully demonstrate and quantify benefit. We will have data from cohorts of patients with long-term follow-up that will demonstrate safety or otherwise. We will have many more technologies available for monitoring and improved methods of transmitting data securely. Although patients expect their health records to be treated with respect, data security has been of greater concern to the media (and therefore politicians) than to patients themselves. However, malicious interference with the transmission of data on which treatment decisions are based is a matter of real rather than imaginary concern. In 5 years, HTM programs and conventional care services may also be better integrated. Necessarily, the trials of invasive monitoring conducted to date have focused on those patients with well-defined, usually single, pathologies who are at high risk of events. The extent to which complex (and expensive) monitoring equipment might be beneficial to patients who are more typically encountered – the elderly and those with multiple comorbidities that cause many readmissions – is uncertain and unlikely to be directly tested. Chronic disease management programs may opt for lowtechnology solutions where patients’ general health and wellbeing can be assessed readily: answers to questions such as ‘how are you feeling?’, together with data on pulse, blood pressure and heart rhythm, might be more helpful in managing an older patient with several coincident chronic conditions than 1031
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Hutchinson, Pellicori, Dierckx, Cleland & Clark
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measuring PA pressure. From this perspective, invasive HTM may have a limited role. However, it may be precisely the older, multimorbid patient that has most to gain from more sophisticated technology that allows treatment to be targeted better at their specific pathophysiology when symptoms become a nearuseless guide to treatment (e.g., the older immobile patients with heart failure and chronic obstructive pulmonary disease whose first warning of decompensation is the development of pulmonary edema).
Financial & competing interests disclosure
JGF Cleland has received research support for telemonitoring from Philips and honoraria for speaking and advice from St Jude Medical. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues • Heart failure is common and prognosis is often poor. It is a major health care burden. • Many effective treatments exist but they are often poorly deployed. • Home telemonitoring could improve the delivery of care. • Hemodynamic monitoring may help optimize therapy; treating the underlying disease rather than symptoms and signs is more likely to alter the natural history of the disease favorably. • Trials investigating therapy guided by invasive hemodynamic monitoring have shown promising results. • Identifying the right patient, the right time to intervene and new therapies to improve hemodynamics are all likely to be the key to the success of a hemodynamic home telemonitoring strategy.
Management System (TEN-HMS) study. J Am Coll Cardiol 2005;45(10):1655-44
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