Inmunoglobulina intravenosa para la miocarditis vírica presunta en niños y adultos
Resumen
Antecedentes
Ésta es una actualización de una revisión anterior. Los informes de casos y las series de casos clínicos han descrito respuestas notables a la inmunoglobulina intravenosa (IgIV) en los pacientes con presunta miocarditis vírica, y su administración se ha hecho cada vez más frecuente.
Objetivos
El objetivo principal de esta revisión fue comparar la supervivencia sin eventos (muerte, necesidad de trasplante cardíaco o colocación de un dispositivo de asistencia del ventrículo izquierdo) de adultos y niños con presunta miocarditis vírica tratada con IgIV versus los que no recibieron IgIV. Un objetivo secundario fue determinar si podría identificarse un grupo de pacientes con presunta miocarditis vírica (con base en la edad, la duración de los síntomas, la acuidad de la aparición de los síntomas, la función cardíaca al momento de la presentación, los resultados virológicos o la presencia o ausencia de evidencia anatomopatológica de miocarditis aguda en la biopsia cardíaca en pacientes en los que se había realizado una biopsia) que podría presentar probabilidades de beneficiarse con la IgIV.
Métodos de búsqueda
Se realizaron búsquedas en CENTRAL, MEDLINE, Embase, DARE, CINAHL, Web of Science Core Collection y LILACS en julio de 2019 y en dos registros de ensayos en noviembre de 2019. Se estableció contacto con los autores de ensayos y se verificaron las listas de referencias de los artículos relevantes. No se aplicaron restricciones de idioma.
Criterios de selección
Se incluyeron estudios cuando (1) los participantes tenían un diagnóstico clínico de miocarditis aguda con una fracción de eyección del ventrículo izquierdo (FEVI) ≤ 0,45; un diámetro diastólico final del ventrículo izquierdo (DDFVI) > 2 desviaciones estándar (DE) por encima de lo normal, o una fracción de acortamiento del ventrículo izquierdo (FAVI) > 2 DE por debajo de la media, con una duración de los síntomas cardíacos < seis meses; (2) los participantes no tenían evidencia de enfermedad cardíaca bacteriana o no infecciosa; y (3) los participantes se habían asignado al azar a recibir al menos 1 g/kg de IgIV versus ninguna IgIV o placebo.
Se excluyeron los estudios cuando (1) los participantes habían recibido inmunosupresión antes de la evaluación del desenlace; o (2) se notificó que el inicio de la miocarditis se produjo < seis meses posparto.
Obtención y análisis de los datos
Dos autores de la revisión de forma independiente examinaron los resultados de la búsqueda y extrajeron los datos. El riesgo de sesgo se evaluó con la herramienta Cochrane "Risk of bias”. Se realizó un metanálisis para dos desenlaces (supervivencia general y mejora en la FEVI) con dos ensayos en adultos. No fue posible realizar otros metanálisis debido a que se incluyeron sólo tres estudios relevantes, y los investigadores analizaron a poblaciones muy diferentes y usaron criterios de valoración distintos.
Resultados principales
En esta actualización se añadieron dos ensayos más a los dos previamente incluidos. Anteriormente se había incluido un ensayo cuasialeatorizado debido a la escasez de evidencia de los ensayos aleatorizados. Sin embargo, con la adición de dos nuevos ensayos aleatorizados, se eliminó de esta actualización.
Para dos ensayos en adultos, el riesgo general de sesgo fue incierto, con evidencia de certeza muy baja para todos los desenlaces. El primer ensayo estudió a 62 adultos con miocardiopatía dilatada de aparición reciente asignados al azar para recibir IgIV o un volumen equivalente de albúmina de 0,1% de forma cegada. No existe seguridad acerca del efecto sobre la supervivencia sin eventos entre los grupos (riesgo relativo [RR] 1,76; intervalo de confianza [IC] del 95%: 0,48 a 6,40). El segundo ensayo estudió 41 adultos con miocarditis aguda asignados al azar a altas dosis de IgIV (1 a 2 g/kg durante dos días) o a ningún tratamiento. El grupo de IgIV informó de un mayor tiempo de supervivencia a los 60 días (sin datos en bruto, P < 0,01), pero la evidencia es incierta. Se agrupó el número de muertes notificadas en ambos ensayos, sin evidencia de una diferencia entre los grupos (RR 0,91; IC del 95%: 0,23 a 3,62; I2 = 31%, evidencia de certeza muy baja).
No está clara la evidencia del efecto del tratamiento con IgIV sobre la FEVI (diferencia de medias agrupada (DM) ‐0,01, IC del 95%: ‐0,06 a 0,05) después de 12 meses y de un marco temporal desconocido. No existe seguridad acerca de los resultados para la capacidad funcional según lo evaluado mediante el consumo máximo de oxígeno a los 12 meses (DM ‐0,80; IC del 95%: ‐4,57 a 2,97). Tampoco existe seguridad acerca de los resultados de los efectos secundarios relacionados con la infusión debido a un IC muy grande (RR 20,29; IC del 95%: 1,25 a 329,93). Por último, hubo evidencia incierta del fracaso de la recuperación completa (RR 0,46; IC del 95%: 0,19 a 1,14). No se informó acerca de la evidencia de mejora en el DDFVI, la fracción de acortamiento del ventrículo izquierdo y el estado de hospitalización en adultos.
En el único ensayo pediátrico incluido, el riesgo general de sesgo fue bajo, con evidencia de certeza muy baja para todos los desenlaces. El ensayo incluyó 86 niños en Egipto que acudieron con miocarditis aguda. Los niños fueron asignados aleatoriamente a 1 g/kg de IgIV diaria durante dos días consecutivos o placebo seguido de una ecocardiografía uno y seis meses después de la aleatorización para el registro del DDFVI y la FAVI. No está clara la evidencia de supervivencia general después de seis meses (RR del riesgo de muerte 0,48; IC del 95%: 0,20 a 1,15). Tampoco estaba clara la evidencia de la mejora del DDFVI y la FAVI después de seis meses (DDFVI DM ‐4,00; IC del 95%: ‐9,52 a 1,52; FAVI sin datos brutos). No se informó de la evidencia de mejora en el FEVI, la capacidad funcional, la recuperación completa y el estado de hospitalización en niños.
Conclusiones de los autores
La evidencia de dos ensayos de certeza muy baja y con riesgo de sesgo poco claro proporciona evidencia contradictoria sobre el uso de IgIV para tratar adultos con presunta miocarditis vírica. Un ensayo informó que el uso de IgIV da como resultado un mayor tiempo de supervivencia a los 60 días, mientras que el otro ensayo encontró que la IgIV no proporciona un beneficio apreciable. La evidencia de una diferencia en la supervivencia sin eventos o en la supervivencia general, el DDFVI o la FAVI es de certeza muy baja en un único ensayo pediátrico con riesgo de sesgo bajo. Hasta que estudios de calidad más alta con bajo riesgo de sesgo y tamaños muestrales más grandes demuestren un beneficio en un grupo concreto de pacientes, no está clara la evidencia acerca de la IgIV para la presunta miocarditis vírica. Los estudios adicionales de la fisiopatología de la miocarditis darían lugar a una mejoría en los criterios de diagnóstico, lo cual facilitaría la investigación futura.
PICO
Resumen en términos sencillos
Inmunoglobulina intravenosa para la miocarditis vírica presunta en niños y adultos
Antecedentes
La miocarditis aguda es la inflamación del corazón y se cree que comienza más comúnmente como una infección vírica. La enfermedad afecta a individuos de todas las edades. Con base en múltiples informes de casos y series de casos clínicos, la inmunoglobulina intravenosa (IgIV) se ha convertido en parte de la práctica habitual para el tratamiento de los adultos y los niños con miocarditis aguda en muchos centros.
Resultados
Esta es la segunda actualización de una anterior revisión que encontró un ensayo controlado aleatorizado (ECA) (un tipo de estudio en el que los participantes son asignados a uno de dos o más grupos de tratamiento mediante un método aleatorio) de 62 adultos que sugirió que la IgIV no resulta útil en la miocarditis. La evidencia de esta actualización está actualizada hasta el 2 de julio de 2019, momento en el que se añadieron dos estudios: un ECA de 86 niños que no encontró ninguna evidencia de que la IgIV aumente la supervivencia en comparación con el placebo, y un ECA de 41 adultos que no encontró evidencia de una mayor supervivencia (menos mortalidad), pero informó de que los pacientes vivieron más tiempo en el grupo tratado con IgIV en comparación con el grupo no tratado. Después de reunir los datos disponibles, hubo evidencia incierta del efecto de la IgIV en la prevención de la mortalidad. Se necesita más evidencia de ECA antes de que la IgIV pueda recomendarse sistemáticamente para los adultos o los niños con miocarditis.
Authors' conclusions
Summary of findings
| Intravenous immunoglobulin compared with placebo or no treatment for adults with acute myocarditis | ||||||
| Patient or population: adults with acute myocarditis Settings: hospital Intervention: IVIG Comparison: placebo or no treatment | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Control | IVIG | |||||
| Event‐free survival (risk of death, cardiac transplant, or left ventricular assist device) ‐ adults with myocarditis, median follow‐up of 23 months | 103 per 1000 | 182 per 1000 (50 to 662) | RR 1.76 (0.48 to 6.40) | 62 (1) | ⊕⊝⊝⊝ | |
| Overall survival (risk of death) ‐ adults with myocarditis, median follow‐up of 3.5 months | 182 per 1000 | 165 per 1000 (42 to 658) | RR 0.91 (0.23 to 3.62) | 103 (2) | ⊕⊝⊝⊝ | |
| Side effects ‐ mild infusion effects, 12‐month follow‐up | 0 per 1000 | 2 per 1000 (0 to 33) | RR 20.29 (1.25 to 329.93) | 62 (1) | ⊕⊝⊝⊝ Very low1,5,6 | No control participants reported side effects; baseline risk was estimated to be 0.01% based on the limited data available. For the data reported NNTH = 3. |
| *Basis for assumed risk was calculated by the number of events in the control group reported for each survival outcome. For side effects, no events were reported in the control group. To estimate baseline risk we assumed a low baseline risk of 0.01% based on the limited data available for that outcome. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; IVIG: intravenous immunoglobulin; NNTH: number needed to treat for an additional harmful outcome; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded by 1 level due to unclear risk of bias related to lack of clarity around randomisation and blinding. | ||||||
| Intravenous immunoglobulin compared with placebo or no treatment for children with acute myocarditis | |||||
| Patient or population: children with acute myocarditis Settings: hospital Intervention: IVIG Comparison: placebo or no treatment | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | |
|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | ||||
| Control | IVIG | ||||
| Overall survival (risk of death) ‐ children with myocarditis, 6‐month follow‐up | 295 per 1000 | 142 per 1000 (59 to 340) | RR 0.48 (0.20 to 1.15) | 86 (1) | ⊕⊝⊝⊝ |
| *Basis for assumed risk was calculated by the number of events in the control group reported for each survival outcome. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; IVIG: intravenous immunoglobulin; RR: risk ratio | |||||
| GRADE Working Group grades of evidence | |||||
| 1Downgraded by 2 levels for imprecision due to optimal information size not being met and CI including both appreciable benefit and harm. | |||||
Background
Description of the condition
Acute myocarditis is a disease that occurs in individuals of all ages. It is presumed to usually start as a viral infection, although autoimmune and idiopathic forms also occur. It remains unclear whether the primary problem is most commonly ongoing damage from a virus, a postinfectious inflammatory reaction, or a combination of the two.
One problem involved in analysing the literature on the treatment of patients with acute myocarditis is that the enrolment criteria for these studies are far from uniform. Reasons for this include the following.
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No reference standard has been accepted for the diagnosis of acute myocarditis. Detection of pathogens from cardiac tissue would represent evidence in favour of infectious myocarditis. This seldom occurs, presumably because the concentration of pathogens is typically very low by the time a biopsy is performed. The yield is improved by molecular techniques (Guglin 2012). However, it is not clear whether detection of latent viruses such as cytomegalovirus in cardiac tissue is always indicative of myocarditis. It has been suggested that one way to diagnose acute myocarditis is to perform cardiac biopsies at a minimum of five sites to look for histology fulfilling the Dallas criteria. These criteria require evidence of lymphocytic infiltration and myocyte necrosis with or without degeneration (Towbin 2001). However, studies have shown that biopsies on about half of adults with acute myocarditis at autopsy did not fulfil the Dallas criteria (Towbin 2001). The reason for this is that inflammation can be patchy or transient, and can progress to fibrosis (which would not be interpreted as acute myocarditis) (Levi 2001). Consequently, many studies include patients who do not fulfil the Dallas criteria for acute myocarditis. Alternative World Heart Federation criteria require a diffuse, focal or confluent infiltrate of ≥ 14 leucocytes/mm2 (primarily lymphocytes with up to 4 macrophages/mm2 permitted) (Maisch 2002; Maisch 2013; Meyer 1997). Progress has been reported in the use of diagnostic imaging for diagnosis of acute myocarditis. The 'Lake Louise criteria' can be applied to cardiac magnetic resonance imaging (MRI) for the diagnosis of acute myocarditis (Friedrich 2009). As with an endomyocardial biopsy, the sensitivity of cardiac MRI is greatest if performed early in the course of myocarditis. MRI cannot distinguish viral from other forms of acute myocarditis, but MRI‐guided biopsies have a higher yield than blinded biopsies (Guglin 2012).
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The nomenclature of myocarditis is not yet standardised. For example, the term 'acute myocarditis' is used by some study authors to refer to all cases of active myocarditis (Fuse 2000), whereas other study authors use the term only for disease of indistinct onset, using the term 'fulminant' for cases with a distinct onset and clear evidence of a recent viral illness (Hare 2001). Some study authors use the term 'acute myocarditis' for a presumed infectious process, but others include non‐infectious entities. Some experts believe that infectious myocarditis progresses from a phase where viral infection dominates to a phase where autoimmunity dominates (Liu 2001). If viral replication or cytokine production persists, the patient develops a dilated cardiomyopathy (Liu 2001). If viral replication and cytokine production cease, the patient spontaneously recovers. An alternate viewpoint is that the disease begins as rapidly progressive, acute, or chronic myocarditis, and that these three presentations are not part of a continuum (Fenoglio 1983). Because no agreement has been reached on the natural history of acute myocarditis, and no uniform classification scheme has been devised, it is not possible for studies to consistently report results of treatment for different types of myocarditis.
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No consensus has been reached regarding which investigations must be done to exclude non‐infectious causes of acute myocardial dysfunction. In previously well paediatric patients, a clinical diagnosis of infectious myocarditis is fairly accurate, although congenital cardiomyopathy can present acutely. In adults, ischaemic heart disease is commonly confused with viral myocarditis. Other causes of acute cardiac dysfunction include drug‐induced dysfunction (from alcohol, organic solvents, cocaine, or chemotherapeutic or cardiac agents), collagen vascular disease, and postpartum cardiomyopathy.
It is not clear how acute myocarditis in children differs from acute myocarditis in adults. However, one study showed that 17 of 18 adults with fulminant myocarditis survived (McCarthy 2000), whereas a paediatric study described survival in only two of nine infants with fulminant myocarditis (Mounts 2001).
Description of the intervention
Intravenous immunoglobulin (IVIG) is a pooled blood product that contains a mix of antibodies taken from the blood of healthy donors. It is a type of immunotherapy.
How the intervention might work
If ongoing infection is the primary problem, IVIG could be efficacious if it contains antibodies to the microbe. IVIG also has anti‐inflammatory properties, so it could be efficacious even if the primary problem is a postinfectious inflammatory reaction or a non‐infectious process.
Why it is important to do this review
Multiple case reports, Nigro 2001; Takeda 1998; Tedeschi 2002, and case series, Alrabate 2013; Drucker 1994; Goland 2008; Haque 2009, have described apparent dramatic responses to IVIG in adults and children with acute myocarditis, with one large case series suggesting no benefit irrespective of severity of illness (Klugman 2009). However, results from a randomised controlled trial showed no advantage in IVIG‐treated adults with recent‐onset dilated cardiomyopathy (or in the subgroup with histological evidence of acute myocarditis) (McNamara 2001).
Objectives
The primary objective of this review was to compare event‐free (death, requirement for a cardiac transplant, or placement of a left ventricular assist device) or overall (death) survival of adults and children with presumed viral myocarditis treated with IVIG versus those who did not receive IVIG. A secondary objective was to determine if a group of patients with presumed viral myocarditis could be identified (on the basis of age, duration of symptoms, acuity of onset of symptoms, cardiac function at presentation, virological results, or the presence or absence of histological evidence of acute myocarditis on cardiac biopsy in patients in whom a biopsy was performed) who would be the most likely to benefit from IVIG.
Methods
Criteria for considering studies for this review
Types of studies
This review included randomised controlled trials (RCTs) that compared study participants treated with IVIG versus participants who did not receive IVIG.
We did not include trials that compared IVIG versus immunosuppressive therapy, as tremendous variability has been noted in the type and dose of immunosuppressive drugs used and in the timing of administration of these drugs. However, if arms of a trial included an IVIG group and a placebo or no‐therapy group, participants from these arms were considered for inclusion in this review if possible.
Types of participants
Inclusion criteria
We included inpatients and outpatients of any age, sex, or race.
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Participants had to have a clinical diagnosis of acute myocarditis and at least one of the following:
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left ventricular ejection fraction (LVEF) ≤ 0.45;
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left ventricular end‐diastolic diameter (LVEDD) > 2 standard deviations (SDs) above the norm as adjusted for body surface area;
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left ventricular shortening fraction (LVSF) > 2 SDs less than the mean as adjusted for age, or < 29% in an adult.
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The duration of cardiac symptoms before randomisation had to be < 6 months.
As a result of the poor sensitivity of cardiac biopsy as a diagnostic tool for acute myocarditis, and the fact that biopsies are seldom performed in children with suspected myocarditis, a histological diagnosis was not required.
Exclusion criteria
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Participants could not have any evidence of non‐infectious or bacterial cardiac disease.
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Studies that included participants who had received immunosuppression before the final assessment of outcome following IVIG/no IVIG were excluded, as the benefit of immunosuppression remains controversial.
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As the pathogenesis of postpartum cardiomyopathy is likely to differ from that of other cases of acute myocarditis, participants were excluded if onset of myocarditis was reported to be less than six months postpartum.
Types of interventions
Standard therapy for myocarditis is supportive care. In addition to this, participants must have been randomly assigned to receive at least 1 g/kg of any standard formulation of IVIG versus either placebo or no additional therapy.
Types of outcome measures
We planned to analyse outcome measures using the longest follow‐up time reported for each study. We planned to analyse all outcome measures separately in the subgroup of participants who had cardiac biopsies that fulfilled the Dallas or World Heart Federation criteria for acute myocarditis (Aretz 1987; Maisch 1999; Maisch 2000).
Reporting one or more of the outcomes listed here was not an inclusion criterion for the review. Where a published report did not appear to report one of these outcomes, we accessed the trial protocol and attempted to contact the trial authors to ascertain whether the outcomes were measured but not reported. Relevant trials that measured these outcomes but reported no data at all, or data not in a useable format, were included in the review as part of the narrative.
Primary outcomes
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Event‐free survival, measured as risk of death or the requirement for cardiac transplant or placement of a left ventricular assist device.
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Overall survival, measured as risk of death.
Secondary outcomes
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Improvement in LVEF. We planned to examine change from baseline and look for the presence or absence of normalisation.
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Improvement in LVEDD. We planned to examine change from baseline and look for the presence or absence of normalisation.
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Improvement in LVSF. We planned to examine change from baseline and look for the presence or absence of normalisation.
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Improvement in functional capacity (as determined by increased exercise tolerance as measured by any objective test and the New York Heart Association Functional Capacity test).
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Occurrence of side effects.
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Failure to attain complete recovery.
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Hospitalisation status.
Search methods for identification of studies
Electronic searches
We re‐ran search strategies from the previous searches in 2009 (Appendix 1) and 2014 (Appendix 2) on 2 July 2019 (Appendix 3). We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (via CRS Web) and the Database of Abstracts of Reviews of Effects (DARE) (2015, Issue 2 of 4: last issue available), MEDLINE and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations and Daily (Ovid, 1946 to 27 June 2019), Embase (Ovid, 1980 to Week 26 2019), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCO, 1937 to 2 July 2019), Web of Science Core Collection (Thomson Reuters, 1900 to 2 July 2019), and the Latin American and Caribbean Health Science Information database (LILACS) (BIREME, 1982 to 2 July 2019).
The Cochrane sensitivity‐maximising RCT filter was applied to MEDLINE; for Embase, terms as recommended in the Cochrane Handbook were applied (Lefebvre 2011). An adaptation of the RCT filter was applied to all other databases, except CENTRAL and DARE.
We did not limit the search by language or publication status, and included all years available for each database.
Searching other resources
We reviewed the reference lists of all included studies for further studies.
We searched the following clinical trial registers in January 2014:
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National Heart, Lung, and Blood Institute (www.nhlbi.nih.gov/index.htm);
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ISRCTN Register (www.controlled-trials.com);
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Clinicaltrials.gov (clinicaltrials.gov);
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National Research Register Archive and National Institute for Health Research (NIHR) Portfolio Database (portal.nihr.ac.uk);
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CenterWatch (www.centerwatch.com/search.asp);
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CardioSource (www.cardiosource.com);
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www.neri.org/html/research/clinical/pediatric.asp (to 2003).
For this update we searched the following clinical trial registers on 4 November 2019:
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US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov);
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World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (www.who.int/ictrp/en/).
Data collection and analysis
Selection of studies
Two review authors (JR, MS) independently examined the titles and abstracts of trials generated by the search to identify those that were potentially relevant. We obtained the full‐texts of those studies deemed potentially relevant, and two review authors (JR, MS) assessed these for inclusion in the review using a standardised form. We planned to resolve any discrepancies through discussion.
Data extraction and management
Two review authors (JR, MS) independently extracted data using a standard data form to capture the following information.
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Study characteristics (e.g. design, quality, funding source).
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Study participants (e.g. age, severity of illness, duration of symptoms, number of participants randomised, followed up, and analysed).
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Intervention (e.g. dose of IVIG).
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Outcome measures (e.g. event‐free survival, overall survival, LVEF, LVEDD, LVSF, functional capacity, side effects, complete recovery, hospitalisation status).
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Results.
We noted no discrepancies in data extraction. We requested additional unpublished data from the primary author of one included trial (McNamara 1997).
Assessment of risk of bias in included studies
Two review authors (JR, MS) independently assessed all included studies using the Cochrane 'Risk of bias' tool (Higgins 2011). We determined overall risk of bias based on the primary outcome (event‐free survival or overall survival) within each study. We assessed the risk of bias according to the following seven domains:
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random sequence generation;
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allocation concealment;
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blinding of participants and personnel;
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blinding of outcome assessment;
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incomplete outcome data;
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selective outcome reporting;
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other bias.
We graded each potential source of bias as high, low, or unclear and provided a quote from the study report together with a justification for our judgement in the 'Risk of bias' table. We summarised the 'Risk of bias' judgements across different studies for each of the domains listed. Where information on risk of bias related to unpublished data or correspondence with a trialist, we noted this in the 'Risk of bias' table. The domains were all weighted equally, and disagreements were resolved by consensus.
Measures of treatment effect
Dichotomous data (e.g. event‐free survival, overall survival, occurrence of side effects, complete recovery) were expressed as risk ratio (RR) with 95% confidence intervals (CIs). We measured event‐free survival as risk of an event (death, cardiac transplant, placement of a left ventricular assist device) occurring; overall survival as the risk of death; side effects as the risk of side effects occurring; and recovery as failure to attain complete recovery. We derived the number needed to treat for an additional harmful outcome (NNTH) to help clarify the extent of adverse effects. We converted continuous data (e.g. change in LVEF, change in LVEDD, and peak oxygen consumption) to mean differences (MDs) with 95% CIs.
Unit of analysis issues
We planned to analyse cluster‐randomised trials in accordance with the guidance in Section 16.3.2 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019), but no such studies have as yet been identified. We planned that for trials with multiple arms, we would divide the control group N by the number of arms to avoid double‐counting in meta‐analyses; however, this was not applicable to the studies included in the review.
Dealing with missing data
We contacted investigators or study sponsors in order to verify key study characteristics and to obtain missing numerical outcome data where possible (e.g. when a study was identified as abstract only).
Assessment of heterogeneity
We inspected forest plots visually to consider the direction and magnitude of effects and the degree of overlap between confidence intervals. We used the I2 statistic to measure heterogeneity amongst the trials in each analysis, but acknowledge that there is substantial uncertainty in the value of I2 when there is only a small number of studies. We also considered the P value from the Chi2 test.
We planned that if we identified substantial heterogeneity (50% to 90%), we would report it and explore possible causes by prespecified subgroup analysis. Where heterogeneity was considerable (75% to 100%), we would not pool studies statistically but present them in forest plots and suppress the summary effect estimate.
Assessment of reporting biases
Due to the small number of included studies, we were only able to conduct one meta‐analysis. As the meta‐analysis only included two studies, it was not possible to examine publication bias using a funnel plot.
Data synthesis
Meta‐analysis was only possible for two outcomes (overall survival and change in LVEF) with data provided from two adult trials. Other meta‐analyses were not possible because only three trials were included in the review, which enrolled completely different populations and measured outcomes in different ways.
For peak oxygen consumption, we assumed a correlation of 0.5 and used the methods of Follmann to calculate the SDs of the change from baseline estimates (Follmann 1992). McNamara 2001 reported this variable and calculated the value only on the portion of the sample for which data were available (48/62 participants). The study authors did not provide the breakdown of sample size in each group, only a total sample size. They calculated an estimate of sample size in each group by pro‐rating the original group sample sizes to the new total sample size.
Subgroup analysis and investigation of heterogeneity
We prespecified a subgroup analysis of cardiac biopsies that fulfilled the Dallas, Aretz 1987, or World Heart Federation, Maisch 1999; Maisch 2000, criteria for acute myocarditis to investigate possible heterogeneity; however, due to an insufficient number of included studies we could not undertake this analysis.
Sensitivity analysis
We did not undertake a sensitivity analysis due to the limited number of included studies.
Summary of findings and assessment of the certainty of the evidence
We developed 'Summary of findings' tables (summary of findings Table 1; summary of findings Table 2) for both the adult and paediatric populations using the primary outcome of survival (both event‐free survival and overall survival). In order to present a balanced picture of benefits and harms, side effects were also included as an outcome in the adult population; side effects were not reported in children. For each outcome, two review authors (JR, MS) independently applied the GRADE methods to determine the certainty of the evidence as outlined in the GRADE Handbook (Schunemann 2013). We decided whether or not to downgrade the certainty of the evidence one or two levels for each of the five domains (risk of bias, inconsistency, indirectness, imprecision, and publication bias). Any disagreements were resolved through discussion, and all decisions were justified in the footnotes for transparency.
Results
Description of studies
Results of the search
In the updated search in July 2019, we identified 467 unique references of which 15 references were judged as potentially relevant. We excluded 12 studies that were not randomised or did not evaluate IVIG. One study was identified as ongoing. Two new studies met the inclusion criteria, so in addition to the study included in the previous version of the review, three studies are now included in the review (Figure 1) (El‐Saiedi 2013; Kishimoto 2014; McNamara 2001). Agreement between the two review authors was 100% with respect to study relevance.
Study flow diagram.
Included studies
See Characteristics of included studies for further details.
Two randomised trials of IVIG in adults and one in children have been reported to date (El‐Saiedi 2013; Kishimoto 2014; McNamara 2001).
McNamara 2001 was conducted in the USA and published in English. This placebo‐controlled trial evaluated the efficacy of IVIG amongst 62 adults (mean age 43.0 years, SD 12.3 years) with new‐onset (within six months) dilated cardiomyopathy, normal coronary angiography, and LVEF ≤ 0.40. All participants had endomyocardial biopsies, but only 10 had cellular inflammation (four fulfilled the Dallas criteria for myocarditis, three had borderline myocarditis, and three had non‐specific inflammation). Participants were randomly assigned to receive 2 g/kg IVIG or an equivalent volume of 0.1% albumin in a blinded fashion.
Kishimoto 2014 was conducted in Japan and published in English. This multicentre randomised trial evaluated the prognosis of 41 adults (range 19 to 80 years of age) with a clinical diagnosis compatible with acute myocarditis. It is not clear how many participants had cardiac biopsies. Participants presented with an LVEF ≤ 0.40, recent onset of symptoms (less than six months), and no evidence of valvular or ischaemic heart disease. Pretreatment catheterisation with coronary angiography and endomyocardial biopsy was completed in 20 participants. Participants were randomised to two groups: IVIG (1 to 2 g/kg over two days) or no treatment.
El‐Saiedi 2013 was conducted in Egypt and published in English. This randomised placebo‐controlled study evaluated the addition of IVIG to conventional therapy in 86 children (ranging from 4 months to 6 years of age) with acute‐onset dilated cardiomyopathy and an LVSF less than 20%. Children were randomly allocated to receive 1 g/kg IVIG or a placebo of 5% glucose intravenous fluids 10 mL/kg daily for two consecutive days. There was no evidence of differences in clinical parameters at baseline between the two groups with the exception of cardiac enzymes (CPK), which were higher in the placebo group (IVIG: 155.6 ± 33.9 versus placebo: 243.2 ± 34.2; P = 0.002).
Funding for the McNamara study was provided by a pharmaceutical company in the form of an educational grant (McNamara 2001). Funding for the Kishimoto study was provided by grants from the Japanese Ministry of Education, Science and Culture, the Shimizu Immunology Foundation, the All Coffee Association, The Universe Foundation, and the Cardiovascular Research Foundation (Kishimoto 2014). The funding source for the El‐Saiedi study was not specified (El‐Saiedi 2013).
Ongoing studies
See Characteristics of ongoing studies for further details.
We identified a total of three ongoing trials. Results have not yet been reported from the European Study of Epidemiology and Treatment of Cardiac Inflammatory Diseases (ESETCID) (Hufnagel 2000). This trial involves different therapies depending on the expected pathogenesis of myocarditis, and at least one of the study arms involves immunoglobulin therapy. The Immunoglobulin Therapy for Patients With Idiopathic Cardiomyopathy and Endomyocardial Parvovirus B19 Persistence Trial was completed in June 2018; however, no results have been reported (Heymans 2018). A new trial in India of intravenous IVIG in young patients with recent‐onset dilated cardiomyopathy has been registered, but results are not yet available (Marotrao 2018).
Excluded studies
See Characteristics of excluded studies for further details.
We excluded a total of 26 studies for the following reasons: not an RCT (16 studies), different population (6 studies), different intervention (3 studies), and one study, an abstract, did not report any results.
Risk of bias in included studies
Overall risk of bias was unclear in the two adult studies, Kishimoto 2014; McNamara 2001, and low in the paediatric study (Figure 2; Figure 3) (El‐Saiedi 2013).
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Selection bias was unclear across the included studies. Methods of randomisation and allocation concealment were not reported in Kishimoto 2014, and there was a lack of detailed explanation regarding the use of block randomisation and double‐blinding in relation to allocation concealment in McNamara 2001. El‐Saiedi 2013 used a random table block stratified by a clinical centre where allocation was managed by a third party and used a placebo, and was therefore judged as having a low risk of selection bias.
Blinding
Performance bias and detection bias were unclear across the included studies. No blinding was reported in Kishimoto 2014, resulting in insufficient information to determine risk of bias. In McNamara 2001, double‐blinding is mentioned but not explained, therefore this study was judged as at unclear risk of bias. El‐Saiedi 2013 used a placebo, and both groups received the same follow‐up, resulting in a determination of low risk of bias for this domain.
Incomplete outcome data
Attrition bias was unclear across the included studies. El‐Saiedi 2013 did not report the number of participants lost to follow‐up, and whilst the outcome data for the primary outcome were complete in McNamara 2001, measurements of functional capacity were incomplete with no explanation provided. We assessed both studies as at unclear risk of bias for this domain. Kishimoto 2014 reported that "all patients were followed up for a median of 3.5 months after therapy", and Table 1 appears to be complete, resulting in a determination of low risk of attrition bias.
Selective reporting
Reporting bias was unclear across the included studies, as insufficient information was reported in El‐Saiedi 2013 and Kishimoto 2014. McNamara 2001 had a low risk of reporting bias as all prespecified outcomes were reported.
Other potential sources of bias
No other potential sources of bias were noted.
Effects of interventions
See: Summary of findings 1 Intravenous immunoglobulin compared with placebo or no treatment for adults with acute myocarditis; Summary of findings 2 Intravenous immunoglobulin compared with placebo or no treatment for children with acute myocarditis
Survival
The evidence regarding the effect of IVIG on event‐free survival and overall survival in adults (event‐free survival: risk ratio (RR) 1.76, 95% confidence interval (CI) 0.48 to 6.40; very low‐certainty evidence, median follow‐up time of 23 months (range 14 to 41 months); overall survival: pooled RR 0.91, 95% CI 0.23 to 3.62; very low‐certainty evidence) is uncertain (Analysis 1.1; Analysis 1.2) (Kishimoto 2014; McNamara 2001). The Kishimoto study did report longer survival time (defined as time to event) in the IVIG group during an average follow‐up time of 60 days; however, no raw data were reported (P < 0.01) (Kishimoto 2014).
In the paediatric study, evidence for overall survival was uncertain (RR of death 0.48, 95% CI 0.20 to 1.15; very low‐certainty evidence; Analysis 2.1) with a follow‐up time of six months (El‐Saiedi 2013). Event‐free survival was not reported.
Improvement in LVEF
Evidence was uncertain for improvement in LVEF between the IVIG group and the control group for the two adult trials (mean difference (MD) −0.01, 95% CI −0.06 to 0.05) after 12 months, McNamara 2001, and an unknown time frame, Kishimoto 2014 (Analysis 1.3). The overall certainty of the evidence was very low.
Improvement in LVEDD
In the paediatric study, improvement in LVEDD was seen in both the IVIG and control groups after six months, with uncertain evidence of a difference between groups (MD −4.00, 95% CI −9.52 to 1.52; very low‐certainty evidence; Analysis 2.2) (El‐Saiedi 2013).
Improvement in LVSF
In the paediatric study, both the IVIG and control groups showed improvement in LVSF after six months, with uncertain evidence of a difference between groups (no numerical data; very low‐certainty evidence) (El‐Saiedi 2013).
Improvement in functional capacity
The results of functional capacity as assessed by peak oxygen consumption was uncertain at 12 months (MD −0.80, 95% CI −4.57 to 2.97; very low‐certainty evidence) (Analysis 1.4) (McNamara 2001). No other measures of functional capacity were reported.
Side effects
In adults, the evidence for adverse events potentially related to IVIG was uncertain. Adverse events only occurred in the treated group, and all were described as mild infusion reactions (RR 20.29, 95% CI 1.25 to 329.93; NNTH = 3) (Analysis 1.5) (McNamara 2001). In children, a few participants noted flu‐like symptoms, but no major adverse events were reported including hypotension or anaphylaxis (El‐Saiedi 2013). The overall certainty of the evidence was very low.
Failure to attain complete recovery
The evidence regarding the effect of IVIG on whether participants fully recovered was uncertain (RR 0.46, 95% CI 0.19 to 1.14; very low‐certainty evidence) (Analysis 1.6) (Kishimoto 2014).
Hospitalisation status
No evidence regarding hospitalisation status was reported in any of the included studies.
Discussion
Summary of main results
Two adult studies with an unclear risk of bias and one paediatric study with a low risk of bias showed no benefit of IVIG for the primary outcome (transplant‐free or overall survival) (summary of findings Table 1, summary of findings Table 2). However, one of the adult studies reported longer survival time in the first 60 days in the IVIG group (Kishimoto 2014). With regard to secondary outcomes, one adult study showed no improvement in LVEF (McNamara 2001); the paediatric study showed no improvement in LVEDD or LVSF (El‐Saiedi 2013); and one adult study showed no improvement in functional capacity when last measured (McNamara 2001).
Overall completeness and applicability of evidence
There is residual doubt, particularly in the paediatric study, as to whether all enrolled participants truly have acute myocarditis (El‐Saiedi 2013). Whilst the meta‐analysis of overall survival showed low heterogeneity, not all of the participants may have had confirmed myocarditis (McNamara 2001). This, combined with the small sample size and the variation in the eligibility criteria and reported outcomes, means that the results of the three included studies may not be applicable to all adults and children with suspected acute myocarditis.
As acute myocarditis is a relatively non‐specific entity, it is possible that a subset of patients may respond to IVIG. This group might include patients whose disease was precipitated by a specific virus, or patients treated with IVIG early in the course of their illness, when they have ongoing viral replication in the myocardium. Paediatric patients may be more likely to respond, as the chance that an acute cardiomyopathy is due to viral myocarditis is probably greater in children than in adults.
Quality of the evidence
The overall certainty of the evidence was very low. The quality of the evidence was downgraded most often due to an unclear risk of bias, as randomisation methods were unclear or not reported, and for imprecision due to the confidence interval failing to exclude either a benefit or a harm and for failing to meet the optimal information size.
Potential biases in the review process
Eligible studies should be readily identified by the screening process, as the terminology for 'myocarditis' and 'IVIG' are not ambiguous. Given that there is equipoise on the use of IVIG for myocarditis, studies are of great interest and are likely to be accepted for publication if the quality is acceptable.
Agreements and disagreements with other studies or reviews
A major limitation of McNamara 2001 is that it seems likely that at least some of the trial participants may not have had viral myocarditis, as only 10 of 62 had inflammation on cardiac biopsy. However, the primary purpose of the biopsies in this trial may have been to rule out fibrosis, so fewer biopsies were taken than would have been taken had the purpose been to confirm myocarditis. This lack of benefit contrasts with multiple case reports and case series suggesting potential benefit of IVIG in suspected viral myocarditis (Alrabate 2013; Drucker 1994; Goland 2008; Haque 2009; McNamara 1997; Nigro 2001; Takeda 1998; Tedeschi 2002). Spontaneous improvement is common with acute myocarditis and can be rapid or gradual, so the improvement noted in these case series may have been part of the natural history of the disease. The findings from McNamara and colleagues are also incongruent with the results of the second RCT of adults with recent‐onset myocarditis that was added at this update. Kishimoto and colleagues reported longer survival times in participants treated with IVIG; however, due to an unclear risk of bias and concerns about imprecision, the certainty of the evidence was very low (Kishimoto 2014).
A recent review reported decreased in‐hospital mortality and improved LVEF with IVIG in 13 adult and paediatric studies with a control group (Huang 2019). They reported improved overall survival with IVIG for acute fulminant myocarditis; however, all studies but El‐Saiedi 2013 were observational studies. It is unclear why they did not include the McNamara and Kishimoto RCTs (Kishimoto 2014; McNamara 2001).
One of the excluded studies warrants mention, as it may be of interest to the reader (Maisch 2004). This was a controlled trial of cytomegalovirus hyperimmunoglobulin (CMVhlg), rather than IVIG, amongst 35 participants with CMV‐positive myocarditis. The results showed a significant difference between groups in favour of treatment in terms of elimination of CMV‐DNA and infiltrate, and improvement of 1 New York Heart Association (NYHA) class. In a review article, it was stated that data from the Marburg Registry support the notion that IVIG has efficacy for myocarditis due to adenovirus, but that for myocarditis due to parvovirus, IVIG decreases inflammation but does not eradicate the virus (Maisch 2013). However, an ongoing trial in the Netherlands is examining the use of IVIG in adults with chronic cardiomyopathy and detection of parvovirus B19 on endomyocardial biopsy (Heymans 2018).
Study flow diagram.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1: IVIG versus placebo or no treatment in adults, Outcome 1: Event‐free survival
Comparison 1: IVIG versus placebo or no treatment in adults, Outcome 2: Overall survival
Comparison 1: IVIG versus placebo or no treatment in adults, Outcome 3: Change in LVEF
Comparison 1: IVIG versus placebo or no treatment in adults, Outcome 4: Peak oxygen consumption
Comparison 1: IVIG versus placebo or no treatment in adults, Outcome 5: Side effects
Comparison 1: IVIG versus placebo or no treatment in adults, Outcome 6: Failure to attain complete recovery
Comparison 2: IVIG versus placebo or no treatment in children, Outcome 1: Overall survival
Comparison 2: IVIG versus placebo or no treatment in children, Outcome 2: Change in LVEDD
| Intravenous immunoglobulin compared with placebo or no treatment for adults with acute myocarditis | ||||||
| Patient or population: adults with acute myocarditis Settings: hospital Intervention: IVIG Comparison: placebo or no treatment | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Control | IVIG | |||||
| Event‐free survival (risk of death, cardiac transplant, or left ventricular assist device) ‐ adults with myocarditis, median follow‐up of 23 months | 103 per 1000 | 182 per 1000 (50 to 662) | RR 1.76 (0.48 to 6.40) | 62 (1) | ⊕⊝⊝⊝ | |
| Overall survival (risk of death) ‐ adults with myocarditis, median follow‐up of 3.5 months | 182 per 1000 | 165 per 1000 (42 to 658) | RR 0.91 (0.23 to 3.62) | 103 (2) | ⊕⊝⊝⊝ | |
| Side effects ‐ mild infusion effects, 12‐month follow‐up | 0 per 1000 | 2 per 1000 (0 to 33) | RR 20.29 (1.25 to 329.93) | 62 (1) | ⊕⊝⊝⊝ Very low1,5,6 | No control participants reported side effects; baseline risk was estimated to be 0.01% based on the limited data available. For the data reported NNTH = 3. |
| *Basis for assumed risk was calculated by the number of events in the control group reported for each survival outcome. For side effects, no events were reported in the control group. To estimate baseline risk we assumed a low baseline risk of 0.01% based on the limited data available for that outcome. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; IVIG: intravenous immunoglobulin; NNTH: number needed to treat for an additional harmful outcome; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded by 1 level due to unclear risk of bias related to lack of clarity around randomisation and blinding. | ||||||
| Intravenous immunoglobulin compared with placebo or no treatment for children with acute myocarditis | |||||
| Patient or population: children with acute myocarditis Settings: hospital Intervention: IVIG Comparison: placebo or no treatment | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | |
|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | ||||
| Control | IVIG | ||||
| Overall survival (risk of death) ‐ children with myocarditis, 6‐month follow‐up | 295 per 1000 | 142 per 1000 (59 to 340) | RR 0.48 (0.20 to 1.15) | 86 (1) | ⊕⊝⊝⊝ |
| *Basis for assumed risk was calculated by the number of events in the control group reported for each survival outcome. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; IVIG: intravenous immunoglobulin; RR: risk ratio | |||||
| GRADE Working Group grades of evidence | |||||
| 1Downgraded by 2 levels for imprecision due to optimal information size not being met and CI including both appreciable benefit and harm. | |||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Event‐free survival Show forest plot | 1 | 62 | Risk Ratio (M‐H, Random, 95% CI) | 1.76 [0.48, 6.40] |
| 1.2 Overall survival Show forest plot | 2 | 103 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.23, 3.62] |
| 1.3 Change in LVEF Show forest plot | 2 | 103 | Mean Difference (IV, Random, 95% CI) | ‐0.01 [‐0.06, 0.05] |
| 1.4 Peak oxygen consumption Show forest plot | 1 | 48 | Mean Difference (IV, Random, 95% CI) | ‐0.80 [‐4.57, 2.97] |
| 1.5 Side effects Show forest plot | 1 | 62 | Risk Ratio (M‐H, Random, 95% CI) | 20.29 [1.25, 329.93] |
| 1.6 Failure to attain complete recovery Show forest plot | 1 | 41 | Risk Ratio (M‐H, Random, 95% CI) | 0.46 [0.19, 1.14] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Overall survival Show forest plot | 1 | 86 | Risk Ratio (M‐H, Random, 95% CI) | 0.48 [0.20, 1.15] |
| 2.2 Change in LVEDD Show forest plot | 1 | 86 | Mean Difference (IV, Random, 95% CI) | ‐4.00 [‐9.52, 1.52] |
