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Cost–utility analysis of telemonitoring versus conventional hospital-based follow-up of patients with pacemakers. The NORDLAND randomized clinical trial

Introduction The aim of our study was to perform an economic assessment in order to check whether or not telemonitoring of users with pacemakers offers a cost-effective alternative to traditional follow-up in outpatient clinics. Methods We used effectiveness and cost data from the NORDLAND trial, which is a controlled, randomized, non-masked clinical trial. Fifty patients were assigned to receive either telemonitoring (TM; n = 25) or conventional monitoring (CM; n = 25) and were followed up for 12 months after the implantation. A cost–utility analysis was performed in terms of additional costs per additional Quality-Adjusted Life Year (QALY) attained from the perspectives of the Norwegian National Healthcare System and patients and their caregivers. Results Effectiveness was similar between alternatives (TM: 0.7804 [CI: 0.6864 to 0.8745] vs. CM: 0.7465 [CI: 0.6543 to 0.8387]), while cost per patient was higher in the RM group, both from the Norwegian NHS perspective (TM: €2,079.84 [CI: 0.00 to 4,610.58] vs. €271.97 [CI: 158.18 to 385.76]; p = 0.147) and including the patient/family perspective (TM: €2,295.91 [CI: 0.00 to 4,843.28] vs. CM: €430.39 [CI: 0.00 to 4,841.48]), although these large differences—mainly due to a few patients being hospitalized in the TM group, as opposed to none in the CM group—did not reach statistical significance. The Incremental Cost–Effectiveness Ratio (ICER) from the Norwegian NHS perspective (€53,345.27/QALY) and including the patient/caregiver perspective (€55,046.40/QALY), as well as the Incremental Net Benefit (INB), favors the CM alternative, albeit with very broad 95%CIs. The probabilistic analysis confirmed inconclusive results due to the wide CIs even suggesting that TM was not cost-effective in this study. Supplemental analysis excluding the hospitalization costs shows positive INBs, whereby suggesting a discrete superiority of the RM alternative if hospitalization costs were not considered, albeit also with broad CIs. Conclusions Cost–utility analysis of TM vs. CM shows inconclusive results because of broad confidence intervals with ICER and INB figures ranging from potential savings to high costs for an additional QALY, with the majority of ICERs being above the usual NHS thresholds for coverage decisions. Trial registration ClinicalTrials.gov NCT02237404.

In the field of Cardiology, Telemedicine allows consultations with patients through monitoring systems and remote communication analyzing the ongoing heart rates of people with pacemakers, implantable cardioverter defibrillators, cardiac resynchronization therapy and subcutaneous Holter. The use of remote monitoring may save time and efforts to both healthcare professionals and patients, including their informal caregivers, reducing the number of follow up visits to the hospital and reducing the associated costs with patient follow-up, which will help to improve sustainability of healthcare services.
Since 2001 that the first pacemaker of remote monitoring was implanted in Europe, more than 300,000 pacemaker have been implanted around the world. Despite this sharp expansion, the scientific evidence on economic evaluations of pacemaker with remote monitoring is very limited, and in our knowledge, studies including informal costs have not been conducted. Most of the studies have just focused on implantable cardioverter defibrillators and cardiac resynchronization therapy.
Sustainability of cardiology services: economic evaluation in communication and remote monitoring ...

Objective
Analyze the new communication systems and remote monitoring of people with pacemaker implantation in relation to the sustainability of cardiology services in our current society.

Effectiveness Analysis
Open trial, without masking but with randomization. The study sample (n=38) will be composed by all patients who have been implanted with a pacemaker in the Nordland Hospital (Bodø) between 15/08/2014 and 14/03/2015 with a follow up of 6 months. At the same time 2 groups will be formed according to the type of technology installed: a) Intervention group: composed of 19 patients with a remote monitored (RM) pacemaker (PM). b) Control group: formed by 19 patients with a hospital monitored (HM) PM.
During the monitoring period, the same parameters were analyzed in both groups at 3 different times (pre-implant and at months 1 and 6 post-implantation). Instruments are: a) Clinical History. b) Generic HRQOL Questionnaire, EuroQol-5D (EQ-5D). c) Specific Questionnaire on HRQOL in patients with CVD, Duke Activity Index.

Cost Analysis
Qualitative and quantitative design. Costs will be estimated from both the healthcare perspective and the social perspective.
Identification and quantification of healthcare costs: a) In-depth interviews with the heads of the Cardiology Units and Accounting Department. b) Clinical History. c) Information provided by the Accounting Unit.
Identification and quantification of informal costs: a) Principal Caregiver Questionnaire. b) Satisfaction survey. c) Interviews with patients and families.
Economic Impact: a) Construction of a decision tree, which allows to know the alternatives, events and results of applying both types of monitoring. b) Mathematical simulation through cohorts: Markov Model. c) Explore how communication and remote monitoring of pacemaker can provide added value to the sustainability of the current healthcare system. Expected results 1) Patients' perception regarding to their own health at different times: before and after pacemaker implantation. 2) Costs associated with the monitoring of patients with pacemakers.
3) Economic impact of remote monitoring of pacemaker versus hospital monitoring along time.

DESCRIPTION OF THE PROJECT/ DESCRIPCIÓN DEL PROYECTO
Sustainability of cardiology services: economic evaluation in communication and remote monitoring ...

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Aims General objective 1: Analyze the effectiveness of remote monitoring (RM) in patients with pacemaker (PM) implant compared to the hospital mode.

Specific Objectives
1) To analyse the clinical and socio-demographic characteristics of both groups.
2) To assess the health-related quality of life (HRQoL) and patient satisfaction at different times pre and post implant.
General objective 2: Analyze the costs of remote monitoring (RM) versus hospital monitoring (HM), of PM cardiac patients.

Specific Objectives
1) To identify and assess the direct and indirect health costs resulting from the RM system of patients with PM implant and that applied in the hospital.
2) To analyse the costs that both types of monitoring incur in relation to informal care needed by people with pacemaker implants.

General objective 3:
To assess the impact and cost effectiveness in the medium and long-term of RM vs hospital monitoring (HM): Markov's mathematical model.

Specific Objectives
1) To build a decision tree that allows us to know the alternatives, events and results of applying both types of monitoring.
2) To carry out a mathematical simulation through cohorts.
To explore how communication and the remote monitoring of cardiac devices can add value to the sustainability of the current healthcare system.

Originality and innovative aspects of the project
It is an original study since the literature on cost-effectiveness in the remote monitoring of PM are very limited 21 . Most studies have focused on other cardiac devices such as automatic implantable defibrillator (AID) [16][17][18] and cardiac resynchronization therapy (CRT) 19.20 Differentiating and novel aspects will involve: 1. The analysis of a new monitoring in patients with a pacemaker. 2. Assessing the Quality of Life Related to Health and satisfaction of patients with PM. 3. The identification and assessment of both health care costs and costs associated with informal care (including those related to dependency).
The estimation of the economic impact of RM over time compared with the hospital pacemaker mode.
How shall it contribute to the advance of the knowledge Sustainability of cardiology services: economic evaluation in communication and remote monitoring ...

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This study will show the level of efficiency for both society and for the sustainability of the public health services that this new technology has when applied to pacemakers, and also allows us to determine the degree of savings for both the National Health System and to patients and their environment.
The results will be relevant for political decision-making, health service managers, users and providers of heart technologies both in Spain and Norway, and other countries with similar socio-health characteristics. In addition to this study, due to its innovative nature in relation to services for monitoring and remote communication, it may also be useful for other countries, where patient access to hospitals poses a significant effort due to the orography, means of transport used, proximity to the hospital, economic capacity, etc. Note that Norway is a country that has a wide geographical dispersion of the population, and therefore, these systems become even more relevant in order to bring health to the entire population thus ensuring the sustainability of the health system.
Background, conceptual framework, open questions and approaches, including the justification of the importance of the issue to be faced

Economic Evaluation of Health Technologies
Healthcare Technology is understood as the set of drugs, devices and medical or surgical procedures used in healthcare, and the organizational and support systems within which such care is encouraged 22 . Health technology is intended for the prevention, diagnosis, treatment and rehabilitation of specific clinical conditions and to improve the quality of life of individuals and society 23 .
Despite the economic context of reducing the weight of the public sector in most Western countries, health spending has been steadily growing in recent years 24 .
Since the creation of the Agencies of Health Technology Assessment (AHTA) in Europe in the last decade of the twentieth century, the National Institute for Health and Clinical Excellence (NICE) in the UK stands out. Mathematics and its different temporal assessment and simulation models have helped to assess and predict the evolution of a health technology in the short, medium and long term [2][3][4][5] .
The Economic Evaluation of Health Technologies (EEHT) is the main standardized mathematical tool used globally in evaluating the efficiency of a particular technology. This instrument will help to assess the relationship of costs invested in health outcomes obtained 6 , helping different national health systems to consider whether a technology should be funded or not. The techniques used in an economic evaluation are: cost minimization, cost-effectiveness analysis, cost-benefit analysis and cost-utility analysis 2.3 .

Cardiac Pacemakers
A cardiac pacemaker is a device that senses when the heart is beating irregularly. The PM works by sending a constant signal to the heart, so that it beats correctly 25 .
Between implants and replacements, in Spain in 2012, 34,919 PMs were implanted (745.8 PM / million inhabitants) 21 , which contrasts with the 2,333 PM implanted in Norway in 2009 (489 PM/million inhabitants) 26 . The mean age of implanted patients is over 70 years in both cases. Due to the aging population and the increase in life expectancy, the incidence of degenerative diseases increases, which is the cause of most implants. Males represent 57.1% of PMs implanted in Spain 21 , and that percentage reduces to 55.7% in the case of Norway 26 .
Sustainability of cardiology services: economic evaluation in communication and remote monitoring ...

Hospital Monitoring (HM) vs Remote Monitoring (RM)
HM means check-ups that patients with PM have at the specialist's office, where two functions are mainly performed 10.25 : 1) Control problems that patients have with their heart. 2) Assess the proper functioning of the cardiac device.
As a solution to the complexity of monitoring, in recent years new technology has developed that is capable of RM in patients implanted with PMs.
The cardiologist has free access to information from the cardiac device, at any time of day. And if at any given moment, the specialist detects any anomaly they could alert the patient (phone, email, etc.) so that they come to the hospital. Table 1. Advantages and disadvantages of RM 10-13,27,28 .

Advantages Disadvantages
Ease of use, depending on the type of PM implanted.
Increased staff and budget due to the large volume of information generated.
Telematic registration and assessment of the correct functioning of the PM.
It may adversely affect the patient's attitude, since it can be falsely appreciated as an alternative route for absolute and immediate access to care.
Rapid detection of changes in both heart rate and the operation of the device.
Alerts and other information resulting from the RM can alter the perception that the receiving device has on health.
Saves time and effort for both health professionals and patients and their companions.
Increased care for older patients, and more complex.
Decreased costs associated with monitoring the patient.

Cardiovascular diseases are a major cause of mortality and morbidity.
In 2008, non-communicable chronic diseases in people 60 and older, accounted for the greatest burden of disease attributed 95.5% of disability-adjusted life year (DALY), corresponding to 20.4% of cardiovascular diseases (CVD) 29 . Cardiovascular diseases are a major cause of global morbidity and mortality, and are responsible, according to the World Health Organization, for about 16.7 million deaths worldwide (30% of overall mortality) 29 . 25.75% (4.3 million) of these deaths occur in Europe, and 50% in the European Union (EU), which have an estimated cost of 192 billion €/year. Previous studies 7 have indicated that the total cost, 57% is due to health care costs, 21% to productivity losses and 22% to the informal care of people with CVD.

Work overload in pacemaker consultations
There is a work overload in pacemaker consultations due to an exponential increase in the number of implanted cardiac devices and the increase in technological complexity thereof and the software to manage them.
The implantation of a PM needs monitoring (as well as the implanted patient), in which various electrical parameters will be analysed and adjusted in order to check for correct operation, increased longevity, improved quality of life of patients and prolonged survival 12 .
Sustainability of cardiology services: economic evaluation in communication and remote monitoring ...

Insufficient research
Despite the sharp expansion, the scientific evidence on economic evaluations in the remote monitoring of PM is very limited 4.15 and no studies that include informal costs have been found. Most existing studies have focused on AID [16][17][18] and CRT 19.20 .

Interest
To the best of our knowledge this would be a pioneering study, since research to date has focused on the analysis of various cardiac devices, which is different to the purpose of our project. A distinctive and novel feature will be the ability to identify and evaluate the costs associated with informal care -including those related to dependencein patients with pacemaker implants.
This study will show us the cost-effective potential that this new technology has applied to PMs and, if there is an ability for saving for both the National Health System and patients.

Effectiveness Study
The review of Medical Records will provide us with the information necessary for the evaluation of sociodemographic and clinical variables, and those corresponding to the functioning of the PM.
The administration of the EuroQol-5D (EQ-5D) and Duke Activity Status Index questionnaires, will show the patients' perception regarding the quality of life related to health at different pre and post PM implant times.

Study Costs
The in-depth interviews of those responsible for the departments of Cardiology and Accounting both hospitals, coupled with the review of the Medical Records -throughout the study period -will allow us to identify the direct/healthcare costs.
Access to the data provided by the accounting department will provide the healthcare costs associated with the monitoring of such implants.
To quantify the informal costs associated with this type of care, the following instruments will be used: a) Survey on Disability, Personal Autonomy and Dependency to informal caregivers in month 6 (postimplant). b) Satisfaction Survey on patients at month 6 (post-implant), which include aspects related to displacement, informal caregivers and hospital visits.

Economic Impact
It will evaluate the impact and cost-effectiveness in the medium and long term compared to HM and RM. The tools we will use are: 1) To build a decision tree that allows us to know the alternatives, events and results of applying both types of monitoring.
2) Carry out a mathematical simulation through cohorts.
Explore how communication and the RM of cardiac devices can add value to the sustainability of the current healthcare system.
Sustainability of cardiology services: economic evaluation in communication and remote monitoring ...

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Describe how the planned cooperation shall contribute to the success of the project, and how will it benefit each involved part Cooperation between different groups will enable the exchange of knowledge. It will assess whether the use of the same technology applied in two different healthcare systems provides similar data on effectiveness, costs, and cost-effective impact in the medium and long term.
Working together will strengthen links between researchers in both countries, providing the possibility of working in the future together.
The participation of each institution will benefit the project as follows: •

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Currently the project is being developed at the Hospital de Poniente (Almería, Spain). Ended data collection period in both hospitals, the results will be compared.
The project format has been adapted in response to the aspects mentioned above in the field of economic evaluation in cardiology and shall cover the 3 general objectives presented below.

Participants
Nordland Hospital (Bodø) has a catchment population of approximately 180,000 inhabitants. Between 80-90 PM implants/year 26 . The sample of our study was calculated taking into account the following parameters: Margin of error that we would be willing to accept (%) Prior to implantation, the cardiologist will explain the features of both types of patient PM monitoring (including advantages and disadvantages), and depending on their personal characteristics and access to the telephone network, the type of pacemaker they want implanted must be chosen. The choice will be given in all cases, except for: 1) Patients who are unable to understand the RM procedure or do not have relatives who can take care of it and, 2) Patients who reject RM and prefer to attend consultation.
Criteria for participation in the study a) Inclusion criteria: 1) Be 18 years of age, 2) Have a PM implanted in any of the two types of monitoring: RM versus HM and 3) Understand and be able to properly perform self-monitoring at home. b) Exclusion criteria: 1) Be participating in another study and / or 2) Refuse to participate in the study.

Environment
The choice of hospitals -Hospital de Poniente (Spain) / Nordland Hospital (Norway) -is due to the number of implanted pacemakers (80-90PM/year), but they also differ in other respects such as the reference population Hospital de Poniente (256,000 inhabitants) vs Nordland Hospital (180,000 inhabitants), lifestyles, North-South relationship, different health systems, etc.).
These issues and others have motivated us to perform a comparative study of the same technology (remote pacemaker monitoring), applied in two countries at very different priori.  Regardless of the type of monitoring, the parameters to be measured shall be the same. Access to these variables will allow us to obtain the pacemaker values at different times, which, in turn, will let us establish if there are any differences between the two groups.
In the identification of the health-related quality of life (HRQoL) , two questionnaires will be administered: 1. Generic questionnaire, EuroQol-5D (EQ-5D) [29][30][31][32][33] (Annex 1):  It is a tool that creates an index value to be used in studies of cost-effectiveness, especially in the allocation of health resources 31 .
 The following dimensions of health are measured: mobility, self-care, usual activities, pain/discomfort and anxiety/depression.  It is an instrument that assesses the functional capacity of patients with cardiovascular disease.

Sustainability
 It has the ability to predict the quality of life of patients with cardiac disease.
 The following dimensions were measured: functional capacity in domestic, industrial, sexual and recreational or leisure activities.
In both cases:  They will be administered the day before implantation and at months 1 and 6 after surgery.
 The collection of information is done through personalised interviews during hospitalisation, patient attendance to medical examinations and/or telephone interviews.
 The questionnaires have "closed" questions. The same questionnaire regardless of the way in which the information is collected (personal or telephone interview) will be used.
 They are tools commonly used in the Economic Evaluation of Health Technologies 30-35, 37,38 .

Ethical aspects of the research
It meets the precepts of ethics and research set by the Helsinki Declaration of the World Medical Association. In addition, personal data obtained will be confidential and shall be treated in accordance with that established in the laws on the protection of personal data, both in Norway and Spain. The database obtained from this study will be kept for 3 years in order to publicise the results of the research to the scientific community. After this period the database will be destroyed. Attached:

Primary Results
Incidences of complications within the first 6 months after implantation will be assessed. Different events such as complications related to heart function, surgery (problems of stimulation/ detection), arrhythmias, muscle stimulation, and death are included.
Type, cause, duration and response to the cardiac event, monitoring visits. All medical interventions and medication changes related to the occurrence of events will also be collected.

Secondary outcomes
In this section the results of the quality of life perceived by patients with PMs in 3 different times (pre-implant and at 1 and 6 months post-implant) will be collected. And both formal and informal costs, incurred in the same period. This will allow us to compare the cost-effective relationship between HM and RM.
The perceived quality of life was measured using the generic questionnaire EuroQol-5D (EQ-5D) and the specific questionnaire Duke Activity Index. In this we can access the changing perception of health. alcohol, weight, other pathologies, drugs, etc.) and the variables / parameters to monitor, grouped into two groups (dependent and independent variables), will be included. From the characteristics of each of these records and, as an average weighted by the number of individuals comprising it.

Analysis of the sociodemographic characteristics and population clinics
The mean ± standard deviation and range will be calculated to describe continuous variables and proportions for quantitative variables. The differences between both types of cardiac monitoring, from the χ2 test for categorical variables will be compared. Parametric and nonparametric tests will be carried out for continuous variables depending on the normality assumption. In cases in which the assumption of normality cannot be made, the nonparametric Mann-Whitney test for continuous variables will be performed.

EuroQol-5D questionnaire (EQ-5D) and HRQoL Duke Activity Index
HRQoL scores between subgroups of clinical interest (age, sex, functional class, etc.) with proof of Student's t or variance analysis EuroQol-5D were compared, according to the variable being analyzed for components summaries (EQ-5D) and through Mann-Whitney or Kruskal-Wallis nonparametric tests for the Duke Activity Index scores. The confidence level is set at 95%.
A linear regression to evaluate the quality of previous life will be carried out, the final values and, evaluate the differences.

Limitations
In relation to the period of data collection, we must consider the risk that once this period is over, the two groups will not be comparable. To overcome this situation, it is proposed to increase the period of data collection and therefore the study period.
The absence of randomisation makes it difficult to establish causal effects and the degree of internal validity is reduced while increasing the potential for generalisation of the results 39 .
Sustainability of cardiology services: economic evaluation in communication and remote monitoring ...

Methodology
Qualitative and quantitative design, in which the following tools are used: In-depth interviews of those responsible for the Cardiology and Accounting Units, of both hospitals with the aim of identifying medical costs both direct and indirect, which are grouped according to their origin. The identification of the costs associated with informal care will be obtained from the Caregiver Questionnaire belonging to Survey on Disability, Personal Autonomy and Dependency (DPAD) of the National Statistics Institute 40 from Spain adapted for Norway.
DPAD questionnaire allows us to find out: 1) demographic and social characteristics of caregivers, 2) Level of professionalism, 3) Time spent and types of care, 4) Difficulties in providing care 5) Health status and, 6) Professional aspects, family or leisure of those who have had to do without due to engaging in caregiving.
DPAD tool allows the collection of information may be made by personal interview and / or phone to the primary caregivers if any (See Annex 5) 41.42 and will be administered 1 month after implantation of the PM, coinciding with the period in which most of the implanted patients needed the help of a caregiver.
For the collection and evaluation of the corresponding informal costs to the rest of the study period, we will use the following tools: the clinical history, patient interviews and information provided by the accounting unit.
The costs are estimated in terms of real prices of 01/01/2015, taking into account the perspective of the National Health System and from the perspective of society (informal). Consumption of medicines and resources used/patient (including monitoring visits to the hospital, interventions and hospitalisations related to the implant) will be collected.
The result of multiplying the average resource usage with actual prices may be estimated costs / patient.

Data Analysis
To determine the utilisation and unit value of direct costs and indirect costs associated with informal caregivers, the In estimating the costs of informal care, the time they spend in care is taken into consideration. The replacement cost method will be used, which consists in the measuring the costs that the changing of informal carers for professionals would entail. The average cost per hour of home help service in both countries will be taken into account in the assessment of the care. The costs are measured in Euros (€) and effectiveness will be measured in years of quality-adjusted life year (QALY). This index is usually obtained through the generic EuroQol-5D questionnaire (EQ-5D), which is an instrument that is internationally endorsed 2.3 .

Methodology
A Decision Tree will be built which through graphical representations in diagrams will help us show, in a modeled and clear way, all the alternatives, events and results of applying each type of monitoring (remote vs hospital).
Basic aspects to consider in the construction of a decision tree: 1) Type of monitoring (remote vs hospital).

2) Effectiveness (perceived quality of life and satisfaction)
3) Costs (health and informal) 4) Time horizon, divided into study cycles (annual).

5) Software: MS Excel
We have chosen the Markov model mathematical simulation over other instruments because it is one of the main tools in health economics to estimate the costs and developments in the medium and long term of chronic diseases 43.44 .
An analytical model of decision shall be taken both from the health and social perspective that helps us to estimate the evolution in the medium and long term, to provide greater information on the benefits of implementing an intervention and associated costs thereto. Analytical models help decision makers (health, political and social) to systematise the various expected and controllable alternatives. Furthermore, in cases where we are in uncertain situations, they will help us choose the option that maximizes the expected results.

Data Analysis
To analyze the results of the Markov processes, we will use simulation through cohort. The main reason is a very intuitive simulation in which individuals belonging to each cohort must pass over time to other states, being in most cases and less healthy, ending with the death of the subject. The expected outcome in terms of median survival time or stay in a certain state, is estimated by dividing the number of cycles added by the entire cohort between the size thereof 8.40 .
To the sensitivity analysis, globally accepted common sense and guides or checklists will be applied, to remove or correct uncertainties that may arise. Keep in mind that in the evaluation of health technologies, the causes of uncertainty may be due to the variability of the available data, generalisation of the results, and extrapolation of events, and use of inappropriate analytical methods 8,40,41 .