Structured telephone support (STS) for adult patients with chronic heart failure

Safety

Authors: Mirjana Huic, Pernilla Östlund, Romana Tandara Hacek, Jelena Barbaric, Marius Ciutan, Silvia Florescu, Silvia Gabriela Scintee

Summary

Aim: To determine whether treatment with Structured telephone support (STS) in adults with chronic heart failure (New York Heart Association (NYHA) I-IV), without implantable cardiac defibrillators (ICDs), cardiac resynchronization therapy (CRTs) or pacemakers, who have been admitted to hospital at least once for chronic heart failure has impact on patients’ and technical safety (technical reliability).

Methods: A systematic literature search, according to the predefined search strategy (not limited by publication date but limited to English language), was performed according to the Cochrane methodology, in standard medical and HTA databases. Relevant references (after duplicates were removed) were screened and assessed for eligibility independently by two reviewers. References have been included or excluded according to the overall research question, Population-Intervention-Control-Outcome (PICO)-scheme (as described in Project Scope), and the predefined inclusion/exclusion criteria. The quality of the included systematic reviews (SRs) was assessed using AMSTAR tool {Shea 2007}. The results from the included SRs were included according to the methodology suggested by Whitlock 2008 { } and Robinson 2014 { } on how to integrate existing SRs into new SRs. Risk of bias of included RCTs was evaluated independently by two reviewers using the Cochrane risk of bias checklist and EUnetHTA methods guidelines on internal validity of RCTs. Data extraction was performed by one reviewer on pre-defined extraction tables and double-checked regarding completeness and accuracy by a second reviewer. Any differences in extraction results were discussed to achieve consensus; any disagreements were resolved by a third reviewer. Quantitative synthesis from existing SRs were used and presented in Result section when available for specific assessment element questions. No new meta-analysis was performed. Primary outcomes were adverse events (AE): frequency of any AE, serious-SAE, most frequent AE; and discontinuation due AE. A secondary outcome was technical safety (technical reliability).

Results: 591 records were identified through database searching and 28 additional records were identified through other sources; 428 remained after duplicates were removed. One hundred full-text articles were assessed for eligibility and after the exclusion of 76 full-text articles, five high quality SRs and 19 full text published RCTs were included in our SR. Of the included RCTs, only three were judged to be of low risk of bias. In the most recent SR no evidence on potential harms was found on STS interventions. None of 19 included RCTs specifically mentioned adverse events (AEs) as primary or secondary outcomes. In only one RCT which specifically mentioned AEs no adverse events were reported and only one RCT provided explanation on the reason why it did not monitor AEs.

Conclusion: The sources were not sufficient to answer the questions on STS safety in patients with chronic heart failure. No evidence was found to answer technical safety.

Introduction

The Safety Domains describes the direct and indirect harms of a technology for patients, staff and environment, and how to reduce the risk of harms {HTA Core Model Handbook Online, Version 1.5}.

Aim of this assessment was to determine whether treatment with Structured telephone support (STS) in adults with chronic heart failure (New York Heart Association (NYHA) I-IV), without implantable cardiac defibrillators (ICDs), cardiac resynchronization therapy (CRTs) or pacemakers, who have been admitted to hospital at least once for chronic heart failure, has impact on patients’ and technical safety (technical reliability).

More specifically our primary outcomes were adverse events (AE): any AE, serious-SAE, most frequent AE; and discontinuation due AE. A secondary outcome was technical safety (technical reliability).

For this relative effectiveness assessment we planned to find and update recent, high quality systematic review (SR), with PICO (Patient-Intervention-Comparison-Outcome) scheme relevant for this assessment. Whitlock et al. 2008 { } and Robinson et al. 2014 { } in their published articles, regarding how to integrate existing systematic reviews into new systematic reviews, found that consensus among systematic review organizations and the Evidence-based Practice Centers (EPCs) about some aspects of incorporating existing systematic reviews already exist, but areas of uncertainty remain: how to synthesize, grade the strength of, and present bodies of evidence composed of primary studies and existing systematic reviews. According their published data, use of existing systematic reviews may include: (1) using the existing systematic review(s)’ listing of included studies as a quality check for the literature search and screening strategy conducted for the new review (Scan References); (2) using the existing systematic review(s) to completely or partially provide the body of included studies for one or more Key Questions in the new review (Use Existing Search); (3) using the data abstraction, risk of bias assessments, and/or analyses from existing systematic reviews for one or more Key Questions in the new review (Use Data Abstraction/Syntheses), or (4) using the existing systematic review(s), including conclusions, to fully or partially answer one or more Key Questions in the new review (Use Complete Review).

Methodology

Frame

The collection scope is used in this domain.

Assessment elements

Methodology description

A systematic literature search, according the predefined search strategy (Appendix 1) (not limited by publication date but limited to English language), was performed according to the Cochrane methodology {Higgins 2011}, in standard medical and HTA databases.

Information sources

Specifically, the following databases were searched: MEDLINE accessed through OVID or Pubmed; CINAHL with Full Text (EBSCOhost), SCI-EXPANDED (Web of Science^TM Core Collection) and Cochrane Library searching the following databases: The Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Database of Systematic Reviews (Cochrane Reviews), The Database of Abstracts of Reviews of Effects (DARE) and The Health Technology Assessment Database (HTA).

This was complemented by hand search of the following websites: http://www.cadth.ca/en/products/health-technology-assessment; http://www.york.ac.uk/inst/crd/publications.htm; http://guidance.nice.org.uk/Date; http://hta.lbg.ac.at; http://kce.fgov.be; http://www.hiqa.ie/; http://www.agenas.it. The reference lists of relevant systematic reviews and health technology assessment reports were checked for relevant studies.

In addition, the following clinical trials registries were assessed, for registered ongoing clinical trials or results posted: ClinicalTrials.gov, ISRCTN, EU Clinical Trials Register, and International Clinical Trials Registry Platform (ICTRP).

Relevant references (after duplicates were removed) were screened and assessed for eligibility independently by two reviewers. References have been included or excluded according to the overall research question, Population-Intervention-Control-Outcome (PICO)-scheme (as described in Project Scope),  and the inclusion/exclusion criteria listed below:

Q What are the effects of Structured telephone support (STS) on adults with chronic heart failure?

P Individuals aged 16 or more with chronic heart failure (New York Heart Association (NYHA) I-IV), without implantable cardiac defibrillators (ICDs), cardiac resynchronization therapy (CRTs) or pacemakers, who have been admitted to hospital at least once for chronic heart failure

I Structured telephone support (STS)

C Usual care (UC) without Structured telephone support (STS)

O Domain Specific Outcomes: Adverse events (AE) (frequency of any AE, serious-SAE, most frequent AE; discontinuation due AE); technical safety (technical reliability)

Study Design 

D Evidence synthesis studies (SRs, HTA reports) [updating RCTs i.e. RCT fitting the PICO which have been published after the last search date of the latest SR/HTA document]

Inclusion criteria:

1. SRs and HTAs and RCTs comparing chronic heart failure patients management /New York Heart Association (NYHA) I-IV, without implantable cardiac defibrillators (ICDs), cardiac resynchronization therapy (CRTs) or pacemakers, who have been admitted to hospital at least once for chronic heart failure/ delivered via structured telephone support with usual care;
2. Patients should be randomized to structured telephone support or usual care without structured telephone support (STS);
3. One or more of the SAF outcomes were reported;
4. Sufficient methodological details are reported to allow critical appraisal of study quality;
5. Publication in English;
6. Report on humans only.

Exclusion criteria:

Primary or secondary studies which:

1) Do not involve adult patients with CHF /New York Heart Association (NYHA) I-IV, without implantable cardiac defibrillators (ICDs), CRTs or pacemakers, who have been admitted to hospital at least once for chronic heart failure/;  

2)  Do not compare CHF management delivered via structured telephone support with usual care in patients with CHF living within the community;

3) Home visits were performed as part of the intervention or by the clinical staff involved in the intervention

4) Do not provide data for our outcomes of interest in an extractable format;

5) Papers with RCTs without sufficient methodological details to allow critical appraisal of study quality;

6) The papers (publications) published in a language other than English; 

7) Duplicate of original publication.

Differences in selection results were discussed in order to achieve consensus; a third reviewer were involved in case of disagreement. The study selection process was presented according to the PRISMA flowchart {Liberati 2009} (Appendix 2).

Finding and updating a recent, high quality SR (with PICO scheme relevant for this relative effectiveness assessment) was planned. The publications by Whitlock et al. 2008 { } and Robinson et al. 2014 { }, regarding how to integrate existing SRs into new SRs, were used. To answer our research questions all four approaches in using existing systematic reviews, described in Robinson et al. 2014 { }, were used: (1) using the existing SR(s)’ listing of included studies as a quality check for the literature search and screening strategy conducted for the new review (Scan References); (2) using the existing SR(s) to completely or partially provide the body of included studies for one or more Key Questions in the new review (Use Existing Search); (3) using the data abstraction, risk of bias assessments, and/or analyses from existing SRs for one or more Key Questions in the new review (Use Data Abstraction/Syntheses), and (4) using the existing SR(s), including conclusions, to fully or partially answer one or more Key Questions in this SR (Use Complete Review).

Quality assessment tools or criteria

The quality of the included systematic review was assessed using AMSTAR {Shea 2007}.

Risk of bias was evaluated independently by two reviewers using the Cochrane risk of bias checklist and EUnetHTA methods guidelines on internal validity of RCTs {Higgins 2011; EUnetHTA 2013}

Direct evidence related to primary outcomes of our assessment was planned to assess by using the GRADE-methodology {Guyatt 2008}. This approach specifies four levels of quality:

High: further research is very unlikely to change our confidence in the estimate of effect;

Moderate: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimates;

Low: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate;

Very low: we are very uncertain about the estimate.

Analysis and synthesis

Data extraction was performed by one reviewer on pre-defined extraction tables and double-checked regarding completeness and accuracy by a second reviewer. Any differences in extraction results were discussed to achieve consensus; a third reviewer was involved in case of disagreement.

The following information was extracted from included secondary studies (SRs or HTAs):Study general information: Author; Year of publication; Reference number; Study objectives; Study characteristics: Study types included in the review; Number of studies included in the review; Review timeframe; Comparison(s); Patients groups (number of patients and health technology used) in the included studies; Outcomes and follow-up: Main outcomes reported; Main study findings; Conclusions: Authors' conclusions. Please look in EFF Domain (Appendix 3)

The following information was extracted from included primary studies:

Data on Study characteristics (study design, registration number, country and centre, study period, ethics committee approval, sponsor, study methodology); Patient characteristics (age, gender, NYHA I-IV); Outcomes; Intervention; Comparator; Flow of patients; Statistical analysis; Results on primary and secondary outcomes; and Conflict of interest data were extracted. Please look in EFF Domain (Appendix 4)

Quantitative synthesis from existing SRs were used and presented in Resut section wherever appropiate. No new meta-analysis was performed.  

Result cards

Patient safety

Safety risk management

Discussion

Aim of this relative effectiveness assessment was to determine whether treatment with Structured telephone support (STS) in adults with chronic heart failure (New York Heart Association (NYHA) I-IV), without implantable cardiac defibrillators (ICDs), cardiac resynchronization therapy (CRTs) or pacemakers, who have been admitted to hospital at least once for chronic heart failure has impact on patients’ and technical safety (technical reliability).

More specifically, our primary outcomes were adverse events (AE): any AE, serious-SAE, most frequent AE and discontinuation due AE. A secondary outcome was technical safety (technical reliability).

Five existing SRs have been integrated {Feltner et al, 2014; Kotb et al, 2015; Pandor et al, 2013; Inglis et al, 2011; Clark et al, 2007} according to the methodology described in Whitlock et al. 2008 { } and Robinson et al. 2014 { }, into this SR. Additionally, 19 RCTs have been included to answer domain assessment element questions that were not answered by the five SRs. We were faced with already recognized areas of uncertainty: how to appropriately synthesize, grade the strength of, and present bodies of evidence composed of primary studies and existing systematic reviews.

In the most recent SR and HTA {Feltner et al, 2014}  no evidence on potential harms was found on STS interventions.

Also none of 19 included RCTs specifically predefined adverse events (AEs) as primary or secondary outcomes. The same is true for one identified trial in publicly available clinical trial register. Only one RCT specifically mentioned AEs Chaudhry et al, 2010 { } and only one RCT provide explanation the reason why they did not monitor AEs Sisk et al, 2006 { }. Chaudhry et al, 2010 { } in 6 months treatment period, multicenter, randomized, single-blind, low risk of bias controlled trial  with aim  to assess whether telemonitoring would reduce the combined end point of readmission or death from any cause among patients recently hospitalized for heart failure no adverse events were reported. Authors discussed that the primary anticipated adverse event associated with telemonitoring was a delay in seeking care for urgent or emergency situations because of a belief that the telemonitoring data would immediately alert clinicians. Sisk et al, 2006 { }, explained that since both nurse management and usual care involved only services delivered in routine practice, the study did not monitor adverse effects.

Kidholm et al, 2012 { } provide a Model for Assessment of Telemedicine Applications, MAST, a structure for future assessment of telemedicine applications. MAST was tested during 2010–13 in twenty studies of telemedicine applications in nine European countries in the EC project Renewing Health on different chronic diseases: Diabetes Mellitus type 2, COPD and Congestive Heart Failure  {Kidholm et al, 2014}.

In RCT assessed remote monitoring of CHF (only 29 patients were analysed in the control group and 30 in the telemonitoring group) safety data was not mentioned {Dafouluas et al, 2014}.

The whole data of Renewing Health project, on telemonitoring application in patients with all three chronic diseases, has demonstrated that the telemedicine services tested are safe as usual care {Kidholm et al, 2014}.

The findings of our literature search are consistent with other studies who address outcomes reporting bias on safety outcomes.

McLean et al, 2013 { } in their systematic review of systematic review with aim to generate a high level synthesis of the evidence on telehealth care applications showed that there was very little in the systematic reviews specifically concerning patient safety. It was not clear whether adverse events did not occur or whether there was a lack of reporting.

Several studies non-specifically connected with telemedicine interventions have documented underreporting of low-grade AEs, recurrent AEs and inconsistent and incomplete characterization and reporting of high-grade AEs {Scharf et al, 2006; Ethgen et al, 2009; Pitrouet al, 2009}.

In study published by Saini et al, 2014 { } with aim to determine the extent and nature of selective non-reporting of harm outcomes in clinical studies that were eligible for inclusion in a cohort of systematic reviews outcome reporting bias for harms was evident in nearly two thirds of all primary studies included in systematic reviews.

In contrast, in the sample of the RCTs analysed in study published by Huic et al, 2011 { } in which technologies other than pharmaceuticals were presented in 30% of total sample,  serious and non-serious AEs were mentioned in more than 80% of the published articles.

In our assessment the sources were not sufficient to answer the questions due the fact that little evidence was identified on the potential harms of STS. No RCTs were found at all to answer some assessment element questions, like technical safety. Possible limitation of our assessment is that we looked only for SRs and RCTs, and not for prospective observational comparative studies or registries data.

The poor reporting of harms data (safety data is inadequately reported or not reported at all) has major implications for proper judging the benefit-risk ratio.

Limitations of data from published studies are obvious, so further research is needed on safety of STS interventions in chronic heart failure patients. Due another limitation - narrow scope of our assessment, our results are not applicable to patients with chronic heart failure with implantable cardioverter-defibrillators (ICDs), cardiac resynchronisation therapy defibrillators (CRT-Ds) or pacemakers. Hindricks et al. 2014 and Parthiban et al. 2015 recently published data on remote monitoring in this selected group of patients { }.

Several methodological issues should be solved when conducting the RCTs like masking outcome assessment as well as clear description of usual care. Pragmatic RCTs as well as observational real world data should also address this issue. Data reporting should be according evidence-based reporting guidelines, specifically CONSORT Statement extension on better reporting of harms in RCTs and trials assessing nonpharmacologic treatments {Ioannidis et al, 2004; Boutron et al, 2008}.

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Appendices

Please see the appendices in EFF Domain

Appendix 1. Search strategy, June 2015

Appendix 2. Flow chart of study selection

Appendix 3. Characteristics of included secondary studies: Systematic reviews/HTA, main study findings and authors conclusions. Assessing the quality of included SRs – AMSTAR Criteria

Appendix 4. RCTs included in SR of effectiveness and safety: Evidence tables and Risk of bias tables

Appendix 5. List of included studies (RCTs) in the secondary studies (SRs or HTAs)

Appendix 6. List of included studies (RCTs) in this Systematic review of Clinical Effectiveness/Safety with Follow-up duration and Risk of bias

Appendix 7. List of Ongoing RCTs in clinical trials registries