Tipos de estudios

Se consideraron elegibles para su inclusión los ensayos controlados aleatorizados (ECA) y los ensayos aleatorizados grupales, así como la primera fase de los ensayos cruzados (cross‐over). Se consideraron los estudios informados como textos completos, solo como resúmenes y los informes no publicados.

Tipos de participantes

Se incluyó a adultos diagnosticados con EM según los criterios de McDonald o Poser (McDonald 2001; Polman 2011; Poser 1983; Thompson 2018). Se consideraron los participantes con las siguientes formas de EM: EM recurrente‐remitente (EMRR), EM secundaria‐progresiva (EMSP), EM primaria‐progresiva (EMPP) y EM progresiva‐recurrente (EMPR) (Lublin 2014), independientemente del sexo, el momento del diagnóstico o el grado de funcionalidad.

Tipos de intervenciones

Se consideró para la inclusión cualquier tipo de intervención de cuidados paliativos, administrada en cualquier esquema, sola o asociada con medicamentos, durante cualquier período de tiempo. El estudio primario tenía que definir la intervención como paliativa para poder ser incluido en esta revisión. Los posibles tipos de intervenciones incluyeron (pero no se limitaron a): trabajo en equipo multidisciplinario con el objetivo de tratar los síntomas físicos, espirituales y psicosociales; manejo de cómo vivir con una enfermedad potencialmente mortal; y atención avanzada que incluye la discusión del soporte vital avanzado (Murphy 2016).

Los cuidados paliativos se definen como un tipo de tratamiento destinado a mejorar la calidad de vida de los pacientes y las familias que se enfrentan a una enfermedad potencialmente mortal, mediante la detección precoz, la prevención y el tratamiento del dolor y el sufrimiento psicosocial, físico y espiritual. Pueden ayudar a la persona a vivir con la mayor funcionalidad e independencia posible hasta la muerte. Deben integrarse en los sistemas de salud de los países y ofrecerse al principio de la evolución de la enfermedad. Suelen estar a cargo de un equipo multidisciplinario y en diferentes niveles de atención (en el hogar, en la comunidad y en los servicios de cuidados paliativos especializados) (NICE 2004; OMS 2018).

Tipos de medida de resultado

Búsquedas electrónicas

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

• Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (2018, issue 10);

• MEDLINE (www.nlm.nih.gov/bsd/pmresources.html) (1966 to 31 October 2018);

• Embase (www.elsevier.com/solutions/embase‐biomedical‐research) (1974 to 31 October 2018);

• Cumulative Index to Nursing and Allied Health Literature (CINAHL; www.ebscohost.com/nursing/products/cinahl‐databases/cinahl‐complete) (1981 to 31 October 2018);

• Latin American and Caribbean Health Science Information Database (LILACS; lilacs.bvsalud.org/en/) (1982 to 31 October 2018);

• ClinicalTrials.gov (clinicaltrials.gov); and

• World Health Organization (WHO) International Clinical Trials Registry Platform (apps.who.int/trialsearch).

See Appendix 1 for the list of keywords used in the search.

In addition we searched:

• PsycINFO (American Psychological Association (APA) (from inception to 31 October 2018); www.apa.org/pubs/databases/psycinfo/index.aspx); (Appendix 2);

• PEDro (Physiotherapy Evidence Database; www.pedro.org.au) (from inception to 31 October 2018); (Appendix 3);

• Opengrey (European Association for Grey Literature Exploitation ‒ EAGLE; www.opengrey.eu) (from inception to 31 October 2018); (Appendix 4).

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 website (https://msrdcns.cochrane.org/).

Búsqueda de otros recursos

We screened the reference lists of published reviews to identify RCTs that we may not have identified through our electronic searches. We also handsearched the annals of national and international conferences, such as America's 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 contacted specialists in MS and in palliative care to find additional information.

Selección de los estudios

Two review authors (COCL and RLP) independently screened all references retrieved by the search and selected studies for full‐text reading from the titles and abstracts. They consulted a third author (ALCM) in case of disagreement. Two independent authors (COCL and RLP) read the full texts of potentially relevant studies. They included those that fulfilled the aforementioned selection criteria. When necessary, a third author (DVP) resolved disagreements. We recorded the reasons for exclusion of each study.

Extracción y manejo de los datos

The records retrieved by the search were entered into a reference manager program (Mendeley 2017) and this information was transferred to the Rayyan platform (Ouzzani 2016). We identified and excluded duplicates and collated multiple reports of the same study so that each study, rather than each report, was the unit of interest in the review. We recorded the selection process in sufficient detail and completed a PRISMA flow diagram (Moher 2010), and a 'Characteristics of excluded studies' table.

Two review authors (COCL and RLP) independently extracted data from each included RCT using a standardised data extraction form. In case of disagreements, a third author (RR) was involved to reach consensus. When available data were insufficient, we contacted the authors of included studies to obtain additional information (Latorraca 2018 [pers comm]; Latorraca 2018a [pers comm]; Latorraca 2018b [pers comm]; Latorraca 2018c [pers comm]; Latorraca 2018d [pers comm]; Latorraca 2019 [pers comm] ). We extracted 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, objectives, study design, duration of study and follow‐up period, number and location of centres, setting, methods and unit of randomisation, allocation, concealment, blinding.

3. Participants: inclusion and exclusion criteria, method of recruitment, informed consent obtained, total number randomised, baseline imbalances, withdrawals and losses to follow‐up, 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, delivery setting, 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, timing measured and reported, outcome assessors, imputation of missing data, and number of participants in each arm at the end of the study.

6. Notes: funding source, declaration of interest.

Evaluación del riesgo de sesgo de los estudios incluidos

Two review authors (COCL and RLP) independently evaluated risk of bias of each included study according to Cochrane's tool for assessing risk of bias (chapter 8.5, Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011)). They involved a third author (RR) to reach consensus, when 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 planned to judge different outcomes separately. However, we judged blinding of participants and personnel, blinding of outcome assessment and incomplete outcome data at outcome level, but we presented it gathered by study as it was more readable.

We summarised the overall risk of bias for each outcome, following the criteria below:

• Low risk of bias (plausible bias unlikely to seriously alter the results) when all the criteria were classified as at low risk of bias.

• Unclear risk of bias (plausible bias that raises some doubt about the results) when one or more criteria were classified as at unclear risk of bias in the absence of any criteria classified as high risk of bias.

• High risk of bias (plausible bias that seriously weakens confidence in the results) when one or more criteria were classified as at high risk of bias.

Medidas del efecto del tratamiento

For each outcome, we calculated a summary estimate of treatment effects with 95% confidence intervals (CIs) for each comparison. We reported continuous data as mean differences (MDs) and, if the outcome was measured in different scales, standardised mean differences (SMDs). We planned to summarise dichotomous outcomes as risk ratios (RRs) and time‐to‐event outcomes as hazard ratios (HRs).

Cuestiones relativas a la unidad de análisis

The analysis was made at the individual allocation level regardless of study design, parallel or cross‐over. We did not find any cluster‐randomised trials or studies with multiple treatment groups that assessed palliative care interventions for MS.

Manejo de los datos faltantes

In cases of missing or unavailable data, we contacted the corresponding authors of the primary studies for further information. We recorded the answers obtained and the dates of our contacts. We searched for protocols or additional articles (or both) related to the included trials. Where data were missing to the extent that we could not include the study in the meta‐analysis, and attempts to retrieve data were exhausted, we presented the results as qualitative syntheses.

Evaluación de la heterogeneidad

We assessed the following among studies:

• Clinical heterogeneity: we assessed included studies based on characteristics of participants (MS types, comorbidity, and treatments that participants were probably receiving on trial entry); characteristics of the intervention (delivery setting, timing of palliative care, treatment duration); and outcomes (measurement tools and timing).

• Methodological heterogeneity: we assessed the randomisation process, study quality, and analytical methods of the included studies.

• Statistical heterogeneity: we used the Chi² test and the I² statistic. I² values equal to or higher than 50% were considered as indicative of significant heterogeneity between studies in a meta‐analysis (Higgins 2011).

Evaluación de los sesgos de notificación

We did not perform a funnel plot analysis because fewer than ten trials were included in the review (Egger 1997).

Síntesis de los datos

We planned to apply a random‐effects model by default. To assess the robustness of our findings, we planned to conduct sensitivity analyses for primary outcomes using fixed‐effect models (Review Manager 2014). In case of inconsistency between the two models, we planned to present both results; otherwise, we would present only results from the random‐effects model. For outcomes where we could not provide a quantitative analysis, we presented the results of individual studies in a narrative synthesis (qualitative analysis).

Análisis de subgrupos e investigación de la heterogeneidad

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

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

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

Due to the scarcity of studies included in the meta‐analyses, we could not conduct subgroup analyses.

Análisis de sensibilidad

If a sufficient number of studies had been included, we would have undertaken sensitivity analyses, for the primary outcomes, to assess the strength of the results by:

• Excluding from the meta‐analysis studies judged to be at 'high risk of bias' and 'unclear risk of bias' as defined in Assessment of risk of bias in included studies section.

• Excluding from the meta‐analysis unpublished studies.

• Using fixed‐effect models.