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Cochrane Database of Systematic Reviews Protocol - Intervention

Palliative care interventions for people with multiple sclerosis

Authors' declarations of interest

Version published: 23 January 2018 Version history

https://doi.org/10.1002/14651858.CD012936

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view the current version 22 October 2019
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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effects (benefits and harms) of palliative care interventions for patients with any form of MS.

Background

Description of the condition

Multiple sclerosis (MS) is a chronic, disabling and progressive condition that affects around 2.3 million people worldwide (Browne 2014; WHO 2008). The disease is characterised by an autoimmune, inflammatory and demyelinating process of the brain and spinal cord (central nervous system) with progressive loss of neurons and axons (Nylander 2012).

The progressive course of MS and the related functional damage substantially affect patients' daily activities, autonomy and quality of life (WHO 2008). The many symptoms of MS increase patients' emotional, psychosocial and physical burden (Fox 2012).

The disease is associated with high emotional, social and physical impact for patients, caregivers and health systems (Chiaravalloti 2008; Khan 2007; Multiple Sclerosis International Federation 2010).

MS is frequently diagnosed in patients at an age when they are engaged in professional activities for economic self‐sufficiency or family support (WHO 2008).

The course of the disease is unpredictable. According to the most recent definition, the following patterns are reported: clinically isolated syndromes (CIS); radiologically isolated syndrome (RIS); relapsing‐remitting MS (RRMS); secondary‐progressive MS (SPMS); and primary‐progressive MS (PPMS) (Lublin 2014).

Description of the intervention

Current therapies for MS focus on treatment and prevention of exacerbations and on avoiding the progression of disability (Filippini 2013). Therapeutic options include pharmacological and non‐pharmacological approaches, frequently used in combination. Despite the development and approval of new drugs, their effects on disease progression are still modest (Gray 2004; He 2016; La Mantia 2010; La Mantia 2012; Liu 2013; Riera 2016; Rojas 2010). There have been some promising new therapies for patients with RRMS but a cure for patients with progressive MS is not yet available (Fox 2012). In this context, palliative care seems to be a reasonable strategy for MS patients.

Palliative care is defined as the active and total care of pain and psychological, spiritual and social problems of patients with a disease that does not respond to curative treatments (EAPC 1998). Palliative care aims to improve the quality of life of both patients and families. As it is the combination of several components, it may be defined as a complex intervention (Craig 2008).

The objectives of palliative care include the relief of pain and other stressor symptoms; the promotion of the concept of life and death as something natural; promoting respect for the natural course of death; the integration of psychological and spiritual aspects into patient care; the preservation of an active life for as long as possible; giving assistance to families in supporting the patient during the illness and supporting families, after death, in their grief; a team approach to take care of patients' and families' needs; and the improvement of quality of life positively influencing the course of disease (Hui 2013; The WHOQOL Group 1998; WHO 2002).

Palliative care can be delivered by a team of multidisciplinary specialists (medical doctors, nurses, social workers, chaplains, physiotherapists, occupational therapists, dentists, psychologists and psychiatrists) or through an approach coordinated by a specialized professional (usually nurses). Palliative care usually takes place in different settings, such as the community, hospitals, hospices, day‐care units, outpatient clinics and the patient's home (Huan 2014).

Palliative care may be divided into three time‐point categories: early palliative care, when administered at the moment of the diagnosis or within the first eight weeks after diagnosis; palliative care itself, when active treatments are left behind and the patient focuses only on symptom management and quality of life; and end‐of‐life care, when the patient is living his or her last year of life (NICE 2011).

How the intervention might work

There is some evidence about the benefits of palliative care for cancer patients (Gomes 2013; Higginson 2003), but there is a lack of evidence for other conditions, such as neurodegenerative diseases (Karam 2016; Murphy 2016). We believe that this type of care may have a positive impact on the quality of care of MS patients, regardless of disease activity, (i.e. during relapsing or remitting periods), although the strategy offered during different periods will vary according to patient symptoms and needs. Different strategies may be planned to deal with pain and other symptoms, psychosocial and economic issues, end‐of‐life care planning and advance directives (Edmonds 2010; Murphy 2016).

Palliative care teams work through cooperation and coordination of different health care professionals (palliative physicians, palliative nurses, physiotherapists, psychologists, social workers, chaplains) and services. Teams create a treatment plan for the total management of symptoms, supporting patients and families on decision‐making (Strupp 2016).

The MS patient presents complex symptoms (Strupp 2016), giving rise to different types of demands. These demands include how to manage the burden of physical disability as well as how to organize daily life, restructure social roles in family and at work, preserve personal identity and community roles, keep self‐sufficiency in personal care and how to be part of an integrated care network (Strupp 2016).

Palliative care teams are trained to keep open full and competent lines of communication about symptoms and disease progression, advanced care planning and end‐of‐life issues and wishes (Buecken 2012; Strupp 2016).

Taking care of family necessities is also a task for palliative care teams. When a severely ill MS family member dies many feelings emerge, including grief and relief: grief about the loss of a loved relative and relief because that family member is no longer suffering (Wollin 2006). The management of families that live with a patient suffering from a chronic progressive disease can prevent the development of complicated or anticipatory grief or depression (Lobb 2006; Wittouck 2011).

Why it is important to do this review

Despite the research and the development of many interventions aimed at reducing disease activity or slowing the progression of MS, this condition remains a life‐threatening and life‐limiting disease with no cure and highly damaging symptoms for patients and their families.

Some primary studies have assessed the effectiveness of palliative care for MS patients (Strupp 2016). A comprehensive synthesis of these studies will help health care professionals, patients and families to make informed treatment choices when considering palliative care for MS.

Objectives

To assess the effects (benefits and harms) of palliative care interventions for patients with any form of MS.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) and cluster randomised trials will be eligible for inclusion, as well as the first phase of cross‐over trials. We will consider studies reported as full texts or as abstract only and unpublished reports.

Types of participants

We will include adults diagnosed with MS according to the McDonald or Poser criteria (McDonald 2001; Polman 2011; Poser 1983). We will consider participants with any form of MS (relapsing‐remitting, primary‐progressive, secondary progressive or progressive‐relapsing), regardless of gender, time of diagnosis or degree of functionality.

Types of interventions

We will consider for inclusion any type of palliative care intervention, given in any scheme, alone or associated with medications, for any period of time. The primary study must define the intervention as palliative in order to be included in this review. Possible types of interventions include (but are not limited to) multidisciplinary team work aiming at the management of physical, spiritual and psychosocial symptoms; management on how to live with a life‐threatening disease; and advanced care including the discussion of advanced life support (Murphy 2016).

Palliative care is defined as any type of non‐curative treatment or intervention intending to improve the quality of life of patients facing a life‐threatening illness, through the prevention and relief of suffering by the early identification and treatment of pain, psychosocial, physical and spiritual suffering. This type of care is usually delivered by a multidisciplinary team, in different settings (home‐based, hospice, day care, hospitalised care or ambulatory care) (WHO 2002).

Comparisons

We anticipate the following comparisons.

  • Palliative care interventions versus no palliative care intervention.

  • Palliative care intervention versus another type of palliative care intervention: for example, home‐based palliative care interventions versus hospice palliative care interventions.

Types of outcome measures

Primary outcomes

  • Health‐related quality of life.

  • Adverse events.

Secondary outcomes

  • Fatigue.

  • Cognitive function.

  • Disability.

  • Anxiety and depression.

  • Hospital admission.

  • Relapse‐free survival.

  • Sustained disease progression‐free survival.

Method and timing of outcome measurement

  • Health‐related quality of life: assessed by the Multiple Sclerosis Quality of Life scale (MSQOL)‒54 (Vickrey 1995); the Multiple Sclerosis Quality of Life Inventory (MSQLI) (Fischer 1999); or other validated tools.

  • Adverse events: number of participants with at least one adverse event, including (but not limited to) complaints by participants, pain, sleep disturbance or any event considered as adverse by the participant.

  • Fatigue: assessed by the Fatigue Severity Scale or the Fatigue Index Scale (Krupp 1989); or any other validated tool.

  • Cognitive function: assessed by any validated tool, including the Multiple Sclerosis Neuropsychological Questionnaire (Benedict 2003); and the Wechsler Adult Intelligence Scale (WAIS, Wechsler 1997).

  • Disability: change in disability as assessed by the Expanded Disability Status Scale (EDSS, Kurtzke 1983).

  • Anxiety and depression as assessed by the subscales of the Delusion‐States‐Symptoms Inventory (Bedford 1978); or any other validated tool.

  • Hospital admission: number of participants experiencing at least one hospital admission.

  • Relapse‐free survival: defined as newly developed or recently worsened symptoms of neurological dysfunction, lasting longer than 24 hours and objectively confirmed. However, we will consider less stringent criteria and we intend to assess this item separately.

  • Sustained disease progression‐free survival: progression will be considered as a ≥ 1.0‐point increase in the Expanded Disability Status Scale (EDSS) score for participants with a baseline score ≤ 5.0; or a ≥ 0.5‐point increase for participants with a baseline score ≥ 5.5 points; confirmed at six months (Kurtzke 1983). We will consider a 1.0‐point increase in EDSS score confirmed at three months' follow‐up as a surrogate outcome measure of progression.

We will measure the pre‐specified outcomes at the following time‐point intervals: short term (zero to less than one month post‐intervention), intermediate (one month to less than six months post‐intervention), and long term (≥ six months post‐intervention).

Search methods for identification of studies

We will conduct a sensitive literature search to identify studies. Two authors (COCL and RLP) will assess the retrieved studies for inclusion. A third author (ALCM) will, when necessary, resolve disagreements. We will contact the Information Specialist of the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group to create each search strategy. The Information Specialist will not limit search strategies by year of publication, language or publication type.

Electronic searches

The Information Specialist will search the Trials Register of the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group, which, among other sources, contains trials from:

In addition we will search:

Information on the Group's Trials Register and details of search strategies used to identify trials can be found in the 'Specialised Register' section within the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group's module.

We have listed the keywords that we will use to search for trials for this review in Appendix 1.

Searching other resources

We plan to screen the reference lists of published reviews to identify RCTs that we may not have identified through our electronic searches. We also plan to handsearch the annals of national and international conferences, such as Americas Committee for Treatment and Research in Multiple Sclerosis; Congress of the European Committee for Treatment and Research in Multiple Sclerosis; International Congress on Palliative Care; European Association for Palliative Care; and MS and palliative care societies. We plan to contact specialists in MS and in palliative care to find additional information.

Data collection and analysis

Selection of studies

Two review authors (COCL and RLP) will independently screen all references retrieved by the search and select studies for full‐text reading from title and abstracts. They will consult a third author (RR) in case of disagreement. Two independent authors (COCL and RLP or ALCM) will read the full texts of potentially relevant studies. They will include those that fulfil the aforementioned selection criteria in the review. When necessary, they will invite a third author (RR or DVP) to resolve disagreements. We will record the reasons for exclusion of each study.

We will download the records retrieved from electronic searching into a reference manager program such as Mendeley (Mendeley 2017) and transfer this information to Covidence (Covidence 2016). We will identify and exclude duplicates and collate multiple reports of the same study so that each study, rather than each report, will be the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram (Moher 2010), and the 'Characteristics of excluded studies' table.

Data extraction and management

Two review authors (COCL and RLP) will independently extract data from each included RCT using a standardized data extraction form. In case of disagreements, they will involve a third author (RR) in order to reach consensus. When available data is insufficient, we plan to contact the authors of included studies to obtain additional information. We will extract the following information from each study.

  1. Study identification: title, year of publication, contact authors, and publication status (abstract or full‐text report).

  2. Methods: ethical approval, objective, study design, duration of study and follow‐up period, number and location of centres, setting, withdrawals, beginning and end dates, methods and unit of randomisation, allocation, concealment, and blinding.

  3. Participants: participants details, inclusion and exclusion criteria, method of recruitment, informed consent obtained, total number randomised, baseline imbalances, withdrawals and exclusions, age, gender, race/ethnicity, type of MS, previous treatments, comorbidities, diagnostic criteria, and other relevant social and demographic data.

  4. Interventions: number randomised in each group, dose, duration of treatment period, timing, delivery, co‐interventions, and compliance.

  5. Outcomes: primary and secondary outcomes specified and collected, results for all these outcomes (absolute and relative number and rates), definition of outcomes, time points measured and reported, person in charge of measurements and reporting, scales, imputation of missing data, and number of participants in each arm at the end of the study.

  6. Notes: funding for trial, conflicts of interest of trial authors.

Assessment of risk of bias in included studies

Two review authors (COCL and RLP) will independently evaluate risk of bias of each included study according to the Cochrane's tool for assessing risk of bias (chapter 8.5, Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011)). They will involve a third author (RR) to reach consensus, if necessary. The 'Risk of bias' tool covers the following seven domains.

  • Sequence generation: was the allocation sequence adequately generated?

  • Allocation concealment: was allocation adequately concealed?

  • Blinding of participants and personnel: was knowledge of the allocated interventions adequately prevented during the study?

  • Blinding of outcome assessors: was knowledge of the allocated interventions adequately prevented during the study?

  • Incomplete outcome data: were outcome data adequately assessed and accounted for?

  • Selective outcome reporting: were the reports of the study free of any suggestion of selective outcome reporting?

  • Other potential threats to validity: was the study apparently free from other problems that could put it at risk of bias?

Judgement of risk of bias for each domain involves classification into one of three categories: (1) low risk of bias, when we consider the domain described by the study to be adequate; (2) high risk of bias, when we consider the domain described by the study to be inadequate; and (3) unclear risk of bias, when the study does not provide enough information for judgement. For the domains 'blinding of participants and personnel', 'blinding of outcome assessors' and 'incomplete outcome data', we will judge different outcomes separately.

Measures of treatment effect

For each outcome, we will calculate a summary estimate of treatment effect with 95% confidence intervals (CIs) for each comparison. We will report continuous data as mean difference (MD) and, if the outcome was measured in different scales, standardised mean difference (SMD). We will summarise dichotomous outcomes as risk ratios (RRs) and time‐to‐event outcomes as hazard ratios (HRs).

Unit of analysis issues

The unit of analysis will be the individual participant.

Dealing with missing data

In cases of missing or unavailable data, we will contact the corresponding authors of the primary studies for further information. We will record the answers obtained and the dates of our contacts. We will search for protocols or additional articles (or both) related to the included trials. Where data are missing to the extent that we cannot include the study in the meta‐analysis, and attempts to retrieve data are exhausted, we will present the results in the review through qualitative syntheses.

Assessment of heterogeneity

We will assess the following, between studies.

  • Clinical heterogeneity: includes study location and setting, full characteristics of participants, comorbidity and treatments that participants were probably receiving on trial entry. We will consider how outcomes were measured, the definition of outcomes, and how they were recorded. Depending on the extent of clinical diversity, we will either analyse studies separately or present their results using a narrative approach.

  • Methodological heterogeneity: includes assessment of the randomisation process, study quality, and analytical method.

  • Statistical heterogeneity: when studies combined into a meta‐analysis present variations between effect sizes, despite the apparent lack of clinical or methodological heterogeneity, we will analyse through the Chi² test and its extension through the I² statistic. I² values equal to or higher than 50% will be considered as indicative of significant heterogeneity between studies in a meta‐analysis (Higgins 2011).

We will investigate reasons for clinical, methodological or statistical heterogeneity (or combinations thereof) by subgroup and sensitivity analyses.

Assessment of reporting biases

We will contact study authors in an attempt to retrieve any missing outcome data. If 10 or more trials are included, we will use funnel plots to investigate possible publication bias.

Data synthesis

We will create forest plots graphics (quantitative synthesis or meta‐analysis) to summarise data using Review Manager 5 (RevMan 5) software if the included studies do not indicate significant heterogeneity and if all data are available (Review Manager 2014). For outcomes where we cannot provide a quantitative analysis, we will present the results of individual studies in a narrative synthesis (qualitative analysis). We will apply a random‐effects model by default. To assess the robustness of our findings, we will conduct sensitivity analyses for primary outcomes using fixed‐effect models. In case of inconsistency between the two models, we will present both results; otherwise, we will present only results from the random‐effects model.

Subgroup analysis and investigation of heterogeneity

For the primary outcomes, we will perform the following subgroup analyses to verify the consistency of results in different subgroups.

  • Disease type: clinically isolated syndrome, relapsing‐remitting, primary‐progressive or secondary‐progressive.

  • Setting of palliative care: home‐based, hospice‐based, day care‐based, hospital‐based, ambulatory‐based.

Sensitivity analysis

To assess the strength of the results we will perform sensitivity analyses, excluding from the meta‐analysis studies judged to be at 'high risk of bias' and 'unclear risk of bias' (mainly selection bias due to allocation concealment and detection bias due to lack of blinding of outcome assessors). We will also perform sensitivity analyses to assess the robustness of results by excluding unpublished results.

'Summary of findings' table

We will create a 'Summary of findings' table for the following outcomes at long‐term follow‐up:

  • Health‐related quality of life.

  • Adverse events.

  • Fatigue.

  • Cognitive function.

  • Disability.

  • Anxiety and depression.

  • Hospital admission.

We will assess the five GRADE parameters (risk of bias, inconsistency, imprecision, indirectness, and publication bias) to evaluate the quality of the body of evidence as it relates to the studies that contributed data to the meta‐analyses. We will use the methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011); and use GRADEpro software (GRADEprofiler 2011). We will justify all decisions to downgrade or upgrade the quality of the evidence in the footnotes.