Cochrane Database of Systematic Reviews

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Cilliers A, Adler AJ, Saloojee H

Cilliers A, Adler AJ, Saloojee H. Anti-inflammatory treatment for carditis in acute rheumatic fever. Cochrane Database of Systematic Reviews 2015, Issue 5. Art. No.: CD003176. DOI: 10.1002/14651858.CD003176.pub3.

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Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Corticosteroids versus aspirin, Outcome 1 Cardiac disease after 1 year. . . . . . . Analysis 1.2. Comparison 1 Corticosteroids versus aspirin, Outcome 2 Outcome of severe cardiac disease after 1 year. Analysis 2.1. Comparison 2 Individual corticosteroids versus aspirin, Outcome 1 Cardiac disease after 1 year. . . . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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[Intervention Review]

Anti-inflammatory treatment for carditis in acute rheumatic fever Antoinette Cilliers1 , Alma J Adler2 , Haroon Saloojee3 1 Department of

Paediatric Cardiology, Chris Hani Baragwanath Hospital, Johannesburg, South Africa. 2 Department of Non-communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK. 3 Department of Paediatrics and Child Health, University of the Witwatersrand, Johannesburg, South Africa Contact address: Antoinette Cilliers, Department of Paediatric Cardiology, Chris Hani Baragwanath Hospital, PO Bertsham, Johannesburg, 2013, South Africa. [email protected]. Editorial group: Cochrane Heart Group. Publication status and date: Stable (no update expected for reasons given in ’What’s new’), published in Issue 4, 2016. Review content assessed as up-to-date: 17 October 2013. Citation: Cilliers A, Adler AJ, Saloojee H. Anti-inflammatory treatment for carditis in acute rheumatic fever. Cochrane Database of Systematic Reviews 2015, Issue 5. Art. No.: CD003176. DOI: 10.1002/14651858.CD003176.pub3. Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background Rheumatic heart disease remains an important cause of acquired heart disease in developing countries. Although prevention of rheumatic fever and management of recurrences have been well established, optimal management of active rheumatic carditis remains unclear. This is an update of a review published in 2003, and previously updated in 2009 and 2012. Objectives To assess the effects, both harmful and beneficial, of anti-inflammatory agents such as aspirin, corticosteroids and other drugs in preventing or reducing further valvular damage in patients with acute rheumatic fever. Search methods We searched the Cochrane Central Register of Controlled Trials (2013, Issue 9 of 12), MEDLINE (Ovid, 1948 to 2013 October Week 1), EMBASE (Ovid, 1980 to 2013 Week 41) and Latin American Caribbean Health Sciences Literature (LILACS) (1982 to 17 October 2013). We last searched Index Medicus (1950 to April 2001) in 2001. We checked reference lists of identified studies and applied no language restrictions. Selection criteria Randomised controlled trials comparing anti-inflammatory agents (e.g. aspirin, steroids, immunoglobulins, pentoxifylline) versus placebo or controls, or comparing any of the anti-inflammatory agents versus one another, in adults and children with acute rheumatic fever diagnosed according to Jones, or modified Jones, criteria. The presence of cardiac disease one year after treatment was the major outcome criterion selected. Data collection and analysis Two review authors extracted data and assessed risk of bias using the methodology outlined in the Cochrane Handbook of Systematic Reviews of Interventions. Standard methodological procedures as expected by The Cochrane Collaboration were used. Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Main results No new studies were included in this update. Eight randomised controlled trials involving 996 people were selected for inclusion in the review. Researchers compared several steroidal agents such as corticotrophin, cortisone, hydrocortisone, dexamethasone, prednisone and intravenous immunoglobulin versus aspirin, placebo or no treatment. Six trials were conducted between 1950 and 1965; one was done in 1990 and the final study was published in 2001. Overall there were no observed significant differences in risk of cardiac disease at one year between corticosteroid-treated and aspirin-treated groups (six studies, 907 participants, risk ratio 0.87, 95% confidence interval 0.66 to 1.15). Similarly, use of prednisone (two studies, 212 participants, risk ratio 1.13, 95% confidence interval 0.52 to 2.45) compared with aspirin did not reduce the risk of heart disease after one year. Investigators in five studies did not report adverse events. The three studies reporting on adverse events reported substantial adverse events. However, all results should be interpreted with caution because of the age of the studies and the substantial risk of bias. Authors’ conclusions Little evidence of benefit was found when corticosteroids or intravenous immunoglobulins were used to reduce the risk of heart valve lesions in patients with acute rheumatic fever. The antiquity of most of the trials restricted adequate statistical analysis of the data and acceptable assessment of clinical outcomes by current standards. In addition, risk of bias was substantial, so results should be viewed with caution. New randomised controlled trials in patients with acute rheumatic fever are warranted to assess the effects of corticosteroids such as oral prednisone and intravenous methylprednisolone and the effects of other new anti-inflammatory agents. Advances in echocardiography will allow more objective and precise assessments of cardiac outcomes.

PLAIN LANGUAGE SUMMARY Anti-inflammatory treatment in the form of corticosteroids and immunotherapy to prevent heart damage resulting from rheumatic fever This is an update of a review published in 2003 and previously updated in 2009 and 2012. For this latest update, the search was rerun on 17 October 2013, and no new studies were found. Rheumatic fever is a late complication of a type of throat infection caused by streptococcal bacteria. It is an immune system disease that can lead to inflammatory disease of the heart (carditis), joints, brain and skin. Carditis can cause heart failure and death. Various anti-inflammatory drugs have been used to treat carditis, including corticosteroids, aspirin and immunoglobulins (immune therapy using antibodies). No new trials were identified in this update. This review includes eight trials with 996 participants. Evidence shows little effect of corticosteroids over aspirin in preventing cardiac disease after one year (six studies, 907 participants, risk ratio 0.87, 95% confidence interval 0.66 to 1.15). Several steroidal agents such as corticotrophin, cortisone, hydrocortisone and dexamethasone were compared with aspirin before 1966, and prednisone and immunoglobulins were compared with placebo in studies from 1990 and 2001, respectively. Most studies did not report on adverse events, but those that did reported complications due to corticosteroids including weight gain, enlarged facial features and acne. Trials were generally old (six of the eight trials were conducted between 1955 and 1965), small and of poor quality and had high risk of bias. For this reason, results should be interpreted with caution.

BACKGROUND

Pathogenesis Rheumatic fever is a delayed complication of pharyngeal infection with group A beta-haemolytic streptococci. Infection with this organism results in a diffuse inflammatory disease of the heart,

joints, brain, blood vessels and subcutaneous tissue. Carditis is not seen at the time of the streptococcal infection and appears only after a latent period of about three weeks. This serves as evidence against the direct role of streptococcal products in the pathogenesis of rheumatic fever. This latent period parallels the time required for development of an immune response (Abraham 1991). The molecular mimicry between certain parts of the streptococcus and tissues of the host may lead to a cross-reactive im-

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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munity, in which the immune system produces an antibody response to various components of the streptococcal organism, as well as to certain tissues of the patient, particularly the heart. Immunological hyper-responsiveness in some patients, together with disturbed helper and suppressor T-cell function, leads to a complex immune system disturbance, which results in acute rheumatic fever and consequent cardiac damage (Williams 1982). Further evidence of an immunological mechanism for the pathogenesis of acute rheumatic fever is found in the presence of myocardial and endocardial deposits of immunoglobulin and complement in these patients (Kaplan 1964). In addition, rabbit antisera against certain group A streptococci have been shown to react with human heart preparations, indicating cross-reaction between the streptococcus and the human heart (Kaplan 1963). More recently, the pathogenic role of inflammatory cytokines in rheumatic fever in the form of tumour necrosis factor (TNF)-alpha, interleukin (IL)8 and IL-6 has been described (Yegin 1997). Substantial evidence pointing to the inflammatory nature of the disease has resulted in use of anti-inflammatory agents such as corticosteroids and aspirin to treat the disease. Newer therapies such as intravenous immunoglobulin (IVIG) and pentoxifylline have been used to modulate cytokine expression and suppression of activated cytotoxic T cells (Narin 2003; Voss 2001).

recorded annual incidence of around 0.5 cases per 100,000 children of school age. A resurgence in the incidence of rheumatic fever has been reported in industrialised countries such as the intermountain area of the United States (Veasy 1987). In developing countries, rheumatic fever appeared to remain an endemic disease, with annual incidence ranging from 100 to 200 per 100,000 school-aged children (Olivier 2000). In South Africa, a survey of 12,050 school children in 1972 revealed a prevalence rate of rheumatic heart disease of 6.9/1000, with a peak rate of 19.2/ 1000 in children aged 15 to 18 years (McLaren 1975). Rheumatic fever occurred at a much younger age in developing countries, and severe chronic valvular heart disease occurred earlier (Halim 1961; Padmavati 1978). The more recent estimate of the global burden of rheumatic heart disease publication in 2013 critically reviewed the previous burden of disease estimates, suggesting that very few populations worldwide have been sufficiently studied to allow for proper prevalence and incidence estimates. Nevertheless the number of definitive cases of rheumatic heart disease has been shown to remain relatively consistent in recent studies in multiple diverse populations, at a prevalence of three to eight per 1000 (Global Burden 2013).

Diagnosis of rheumatic fever Predisposition and susceptibility Occurrence and spread of the streptococcal organism are influenced by the age of the patient, seasonality and socio-economic conditions. A superimposed genetic predisposition also probably exists (Guilherme 1991; Olmez 1993). Supporting evidence for an underlying immunological susceptibility for developing acute rheumatic fever is found in the higher antibody response observed in rheumatic patients compared with non-rheumatic individuals following administration of influenza vaccine, and the finding of isologous red blood cells in these patients (Barrett 1984). A nonHLA B cell antigen, known as the D8/17 lymphocyte alloantigen, has also been identified in patients with rheumatic fever (Ganguly 1992; Khanna 1989). A test to detect this B cell antigen marker can aid in the diagnosis of rheumatic fever and can help detect siblings who are at risk of developing the disease (Herdy 1992).

Epidemiology The epidemiology of acute rheumatic fever and of its complication rheumatic heart disease has changed since the first assessment of its impact, as recorded in this review for the first time in 2003. The literature at that time indicated that more than 12 million people were affected by rheumatic fever worldwide and approximately 400,000 deaths annually result from rheumatic heart disease (WHO/ISCF 1995). The incidence of rheumatic fever had declined in industrialised countries since the 1950s, with a

The most commonly used criteria for the diagnosis of rheumatic fever include the modified Jones criteria (AHA 1965; Dajani 1992). Diagnosis depends on the presence of events classified as major and minor manifestations of the disease. Concern about over-diagnosis of acute rheumatic fever was the main motivation for the creation of the original Jones criteria almost 60 years ago ( Jones 1944). To increase specificity, these criteria have been revised four times - in 1955, 1965, 1984 and 1992 (Shiffman 1995). The latest revision of the Jones criteria (Dajani 1992) suggests that the probability of acute rheumatic fever is high when the following are found. • Evidence of a preceding streptococcal infection, usually measured by elevation of the antistreptolysin O titre together with: ◦ two major manifestations (arthritis, carditis, chorea, erythema marginatum and subcutaneous nodules); or ◦ one major and two minor manifestations (fever, arthralgia, high C-reactive protein (CRP) or elevated erythrocyte sedimentation rate (ESR) and a prolonged PR interval on electrocardiogram). CRP and ESR are also helpful for monitoring inflammatory activity in patients with acute rheumatic fever. However, the ESR does vary according to erythrocyte count and the presence of concomitant heart failure.

Carditis

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Carditis, the most serious major manifestation of rheumatic fever, may culminate in chronic valvular disease and can lead to heart failure and, ultimately, death. Carditis usually has no associated symptoms and often is identified only during clinical examination of a patient who presents with fever, arthritis or chorea (involuntary, jerky movements of the limbs). Clinical features reflect involvement of various layers of the heart, viz, endocardium, including the valves, the myocardium or the pericardium, and frequently all three layers of the heart. The heart valves are the most commonly affected structures. The presence or absence of carditis is an important determinant of the course and prognosis of acute rheumatic fever. The prognosis worsens with increasing severity of the initial carditis and with recurrences (El-Said 1998). Bed rest contributes to reduced rheumatic activity (Barlow 1990).

Valvular sequelae Rheumatic fever complicates untreated group A beta-haemolytic streptococcal infection in 0.1% to 0.3% of the general population and in 3% of epidemics in closed communities (Siegel 1961); second episode attack rates as high as 65% have been reported (Taranta 1964). Inflammation of components of the heart, such as the mitral and aortic valve leaflets and the chordae of the mitral valve, is the most common manifestation of rheumatic carditis (Ayoub 1995). Recurrent attacks of rheumatic fever result in increasing damage to the valves. Damaged valves may regurgitate (fail to close properly and leak) or may become stenotic (fail to open properly). Mitral regurgitation is the most common heart defect (85%) identified in children and adolescents; it results from fibrosis and contracture of the valve leaflets, which prevents proper apposition during systole. The aortic valve is affected in 54% of patients, and the tricuspid and pulmonary valves in less than 5% (Markowitz 1972).

Treatment controversies Recommended therapies for acute rheumatic fever include bed rest, penicillin and anti-inflammatory agents. Steroids At present, no clear consensus has been reached about the place of steroids in preventing rheumatic heart disease. Some practitioners recommend their use for patients with moderate carditis and heart failure (Abraham 1991; Ayoub 1995; El-Said 1998). Steroids have been shown to favourably affect clinical response while reducing the erythrocyte sedimentation rate. In addition, patients receiving steroids had a shorter hospital stay than those treated with aspirin (Human 1984). Other reports suggest that heart failure in patients with active rheumatic carditis occurs as a result of a haemodynamically severe valvular lesion that can be corrected only surgically - not by giving steroids (Kingsley 1987). Steroids are never a “lifesaving measure” in patients with a severe valvular lesion. It is argued that steroids are likely to make the tissues more friable and the task of the surgeon more difficult. Although steroids are used frequently, their use has not been shown to induce improvement in patients with fulminating rheumatic carditis (Barlow 1990; Kingsley 1987). Aspirin (acetylsalicylic acid) Controversy surrounds the value of aspirin in patients with rheumatic fever. Data from several studies do not show an advantage of steroids over aspirin in the treatment of patients with mild or moderate carditis. It is recommended that aspirin be used in patients with mild or moderate carditis, and that steroids be reserved for patients with severe carditis, particularly those with pancarditis and cardiac failure. Use of steroids in these patients is preferred because steroids produce a more prompt anti-inflammatory effect (Ayoub 1995).

Why it is important to do this review Surgery Open heart surgery is needed in patients with severely regurgitant or stenotic valve lesions. Heart valves can be repaired or replaced, if deemed to be non-repairable. Replacement of the valve with a prosthetic heart valve would require the patient to take anticoagulant treatment, usually in the form of warfarin, for life. The dosage of warfarin is crucial, and close monitoring of blood levels is needed to avoid thrombus formation on the prosthetic valve. Control of warfarin at therapeutic levels is a problem in developing countries, where many patients come from poor urban or rural settings with limited access to adequate medical care. In addition, the cost of heart surgery in patients with severely damaged valves is exorbitant and is a drain on the meagre health resources of poor countries.

Rheumatic heart disease remains a major cause of morbidity and mortality in low-income communities (Olivier 2000). It is clear that antibiotic treatment for streptococcal pharyngitis prevents the development of rheumatic fever (DiSciascia 1980), and that antibiotic prophylaxis prevents recurrence (Massell 1988). However, no consensus has been reached on the optimal management of established active carditis to prevent complications, which may include valvular heart disease and death. In view of the many controversies and uncertainties surrounding the use of anti-inflammatory agents in patients with acute rheumatic fever, an up-to-date systematic review is indicated to clarify the most effective treatment strategy. A glossary of terms used throughout this review is provided in Appendix 1.

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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OBJECTIVES To assess the effects, both harmful and beneficial, of anti-inflammatory agents such as aspirin, corticosteroids and other drugs in preventing or reducing further valvular damage in patients with acute rheumatic fever.

• Valvular lesions developing in participants with previously normal valves. • Worsening of valvular lesions in participants with valves damaged during previous attacks of rheumatic fever.

Secondary outcomes

METHODS

• Reduction in hospital stay. • Rate of decrease of erythrocyte sedimentation rate and/or C-reactive protein.

Criteria for considering studies for this review Search methods for identification of studies Types of studies We included only randomised controlled trials (RCTs) in which participants were randomly assigned to receive anti-inflammatory drugs for acute rheumatic carditis and were followed up for at least three months. We applied no language limitations. Types of participants Trials included children and adults with a clinical diagnosis of a first or new episode of rheumatic fever, based on Jones or modified Jones criteria (AHA 1965; Dajani 1992; Jones 1944), and associated cardiac disease at the time of study enrolment. The diagnosis of cardiac disease was based on the presence of mitral and/or aortic regurgitation and/or pericarditis and/or heart failure identified by clinical examination and auscultation, or echocardiography in later studies. Participants were in-patients, and some were subsequently followed up as out-patients following discharge. Types of interventions Selected studies were those in which the following interventions were compared. • Aspirin versus other anti-inflammatory drugs or placebo. • Steroids versus other anti-inflammatory drugs or placebo. • Other anti-inflammatory drugs versus placebo. • Anti-inflammatory drugs versus no treatment. Therapy included anti-inflammatory drugs of any type, administered by any route (i.e. intravenously, intramuscularly, orally) regardless of dosage or number of doses given. Controls included no treatment (Dorfman 1961), placebo infusion of dextrose and saline (Voss 2001) or placebo tablets (Haffejee 1990). Types of outcome measures

Primary outcomes

We searched for randomised and quasi-randomised trials related to the topic of “Anti-inflammatory treatment of acute rheumatic fever”. We searched the following databases for this update on 17 October 2013. • The Cochrane Central Register of Controlled Trials Register (CENTRAL) (2013, Issue 9 of 12). • MEDLINE (Ovid, 1948 to October Week 1 2013). • EMBASE (Ovid, 1980 to 2013 Week 41). • Latin American and Caribbean Health Sciences Literature (LILACS) (1982 to 17 October 2013). The following searches were not updated and were last searched in 2001 and 2011, respectively. • Index Medicus (1950 to April 2001). • PubMed using the terms “Rheumatic fever and treatment” (2007 to September 2011). We applied no language restrictions. We used the Cochrane sensitivity-maximising RCT filter for MEDLINE (updated search in 2013) (Lefebvre 2011) and an adaptation of this filer for EMBASE. See Appendix 2 for details of the search strategies used in 2013, Appendix 3 for strategies used for the 2011 update and Appendix 4 for the original searches conducted in 2002. We checked references in the identified studies.

Data collection and analysis

Selection of studies One review author (AMC) initially selected 33 papers according to relevance by reviewing titles and abstracts. Two review authors then independently analysed selected studies for predetermined inclusion criteria. We resolved disagreements regarding selection through discussion. We have undertaken three updates since initial publication of the review, and we found none of the 507 references in 2009, none of the 78 references in 2011 and none of the 816 references in 2013 to be eligible for inclusion.

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Data extraction and management We extracted various study characteristics and outcome measures, which we entered onto a predesigned data extraction form as follows. • Methods: study design, method of randomisation, allocation concealment, blinding of investigators, inclusion and exclusion criteria. • Population: recruitment, sample size, age, gender. • Intervention: agent, dose, timing and duration of therapy, co-interventions. • Control: participants, agent and dose. • Outcome: timing of outcome, reported outcomes.

One review author (AMC) initially selected 33 papers, eight of which were included for analysis. We checked a further 507 references in 2009, 78 references in 2011 and 816 references in 2013, and found that none described studies that were eligible for inclusion in the review. Included studies We identified eight randomised controlled trials for this review. We present study details in the Characteristics of included studies table.

One review author (AMC) performed data entry and analysis and checked with a second review author.

Length of trials

Assessment of risk of bias in included studies

Participants

We assessed risk of bias in the following areas using the methodology of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). • Random sequence generation. • Allocation concealment. • Blinding of participants and personnel. • Incomplete outcome data. • Selective reporting.

The eight included studies reported on 966 participants. All studies, except RFWP 1955, included participants with a first episode of acute rheumatic fever. Acute rheumatic fever was diagnosed according to Jones criteria 1944 (RFWP 1955), Jones criteria 1965 (Haffejee 1990; Voss 2001) or Jones criteria 1992 (Voss 2001). The other five studies (CRFSG 1960; CRFSG 1965; Dorfman 1961; Massell 1961; Stolzer 1955) did not state the criteria used but were not excluded from analysis, because, despite this deficiency, it is unlikely that they used criteria other than Jones or modified Jones to make a diagnosis of acute rheumatic fever. Six studies enrolled children as participants, with mean age younger than 12 years in each case (range eight to 11 years) (CRFSG 1960; CRFSG 1965; Dorfman 1961; Haffejee 1990; RFWP 1955; Voss 2001). Massell 1961 did not indicate the age of study participants, and Stolzer (Stolzer 1955) reported on a study population that included adult male airmen only. Five of the studies were conducted in the United States (CRFSG 1960; CRFSG 1965; Dorfman 1961; Massell 1961; Stolzer 1955), one was a joint study between the United States and the United Kingdom (RFWP 1955), one study was reported from New Zealand (Voss 2001) and one from South Africa (Haffejee 1990).

Measures of treatment effect We used risk ratios (RRs) and 95% confidence intervals (CIs) as calculated for dichotomous data. Assessment of heterogeneity • We assessed homogeneity between studies using Chi2 and I tests. We pooled and analysed results using random-effects models. • We explored reasons for heterogeneity and the most appropriate conclusions drawn from the observations. 2

Data synthesis We pooled the data using a random-effects model.

RESULTS

Description of studies

Results of the search

Studies provided long-term follow-up from one to six years.

Inclusion criteria CRFSG 1960 required participants to have moderate to severe carditis and time to treatment within 28 days of onset of the illness; CRFSG 1965 and Voss 2001 included patients with carditis and polyarthritis. Duration of aspirin treatment varied in the CRFSG 1965 study, depending on whether participants presented with carditis or polyarthritis; Dorfman 1961 randomly assigned participants following a diagnosis of acute rheumatic fever and required that therapy be initiated within 18 days of onset of the illness; Haffejee 1990 and Massell 1961 required participants to have a diagnosis of carditis only; RFWP 1955 included three groups, which consisted of participants with a normal heart, participants

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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with carditis and those with preexisting heart disease; Stolzer 1955 required a diagnosis of acute rheumatic fever only. Study size RFWP 1955 was by far the largest study (497 participants), and Haffejee 1990 randomly assigned only 35 participants. Three studies included between 50 and 100 participants (CRFSG 1960; Massell 1961; Voss 2001), and the remaining three studies included between 101 and 160 participants (CRFSG 1965; Dorfman 1961; Stolzer 1955). Interventions Trialists provided a wide range of corticosteroid treatments, including ACTH (corticotrophin), cortisone, prednisone, dexamethasone and hydrocortisone. Dosage, route of administration, interval between symptoms and treatment and duration of treatment varied greatly. Aspirin (acetylsalicylic acid) and placebo were used as comparisons. Two studies (RFWP 1955; Stolzer 1955) examined outcomes of using ACTH and cortisone versus aspirin. Massell 1961 combined four drugs (prednisone, dexamethasone, ACTH and cortisone) into a steroid category and compared this versus aspirin. Separate data were not provided for each drug. The study included five allocation groups. Only participants in groups 4 and 5 who were randomly assigned were included in the analysis. Non-randomly assigned participants in groups 1, 2 and 3 who were given “no therapy”, “small-dose hormone” and “large-dose hormone” were not included in the analysis. Prednisone was compared with aspirin in the CRFSG 1960 and CRFSG 1965 RCTs, whereas Dorfman 1961 chose four treatment groups, which included hydrocortisone alone, aspirin alone, hydrocortisone and aspirin together and “no specific treatment”. Haffejee 1990 examined the outcomes of participants given prednisone versus placebo, and Voss 2001 studied the effects of intravenous immunoglobulin versus placebo. Outcomes All studies provided data on long-term follow-up of at least one year. Chosen outcomes varied between studies. CRFSG 1960 included the presence of both mitral and aortic incompetence on auscultation at one year as the outcome following treatment. CRFSG 1965 specified cardiac outcomes as “heart disease”; Dorfman 1961 assessed participants for the presence of apical systolic murmurs, apical diastolic murmurs and basal diastolic murmurs on auscultation; Haffejee 1990 determined the presence of murmurs, the need for surgery and death at follow-up of 15 months to six years (mean three years and 11 months); Massell 1961 assessed the presence of “signs of rheumatic heart disease at one year”; RFWP 1955 analysed all murmurs, including functional murmurs, present at one year. Only significant apical systolic and basal diastolic murmurs diagnosed on auscultation and detected in this study were

included in the review meta-analysis; Stolzer 1955 made a distinction between the presence of apical systolic, apical diastolic and aortic diastolic murmurs at 14 months, and Voss 2001 assessed the presence of “carditis”, defined by the presence of an aortic or mitral murmur diagnosed clinically, and aortic or mitral regurgitation diagnosed using echocardiography, one year after treatment. Multiple outcomes such as a systolic murmur at the apex and an apical diastolic murmur were documented in several participants. All cardiac outcomes, including murmurs, documented one year after treatment were grouped together as “cardiac disease” in the review meta-analysis. Other outcomes such as ESR, CRP values and duration of hospital stay in response to anti-inflammatory therapy were too varied and inconsistent between studies for performance of a meta-analysis.

Drug duration and dosage Studies used not only different drugs but also various dosages and durations of therapy, for example, prednisone and aspirin were given for 12 weeks by CRFSG 1960; prednisone for one to two weeks and aspirin for eight weeks by CRFSG 1965; hydrocortisone and aspirin for 12 weeks by Dorfman 1961; prednisone and placebo for two to 42 days depending on clinical response by Haffejee 1990; ACTH, cortisone, prednisone, dexamethasone and aspirin for 12 weeks by Massell 1961; ACTH, cortisone and aspirin for five weeks by RFWP 1955; cortisone, corticotrophin and aspirin for six weeks by Stolzer 1955; and IVIG and placebo on four occasions over a 28-day period by Voss 2001. Oral hydrocortisone (Dorfman 1961) was given at a dose of 250 mg/d initially (for 96 hours) depending on whether the participant weighed more or less than 80 lb, and then at 100 mg/d × eight weeks, with subsequent tapering over three weeks. Intramuscular cortisone (Stolzer 1955) was prescribed at a dose of 300 mg/d initially (for one day) and then was tapered over six weeks. RFWP 1955 treated participants with ACTH 120 USP units (for four days) and intramuscular cortisone 300 mg initially (for one day) with doses tapered over six weeks. Prednisone was given at a dose of 60 mg/d initially (for three weeks) and was tapered over nine weeks and given at 3 mg/lb for seven days by CRFSG 1960 and CRFSG 1965, respectively.

Excluded studies We initially excluded 25 studies because they were not randomised trials or did not meet the outcome analysis criteria (see Characteristics of excluded studies). We excluded two RCTs because follow-up was provided for less than three months (Camara 2002; Rowe 1953). Three were review studies (Bywaters 1956; Bywaters 1961; Naik 2002), one was a letter (Marshall 1989), another a retrospective analysis (Uziel 2000), one was a study on people who did not have carditis (Paz 2006) and the remaining 17 studies examined the use of steroidal agents for treatment of acute

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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rheumatic fever in a non-randomised fashion. One study (Herdy 2012) met some of the search criteria regarding use of steroids in patients with rheumatic carditis, but this study was a follow-up retrospective analysis and therefore did not meet inclusion criteria.

Risk of bias in included studies

Random sequence generation All studies claimed to be randomised, but only one was judged to have low risk of bias (Voss 2001). Six did not state how the study was randomised and were at unknown risk of bias (CRFSG 1960; CRFSG 1965; Dorfman 1961; Haffejee 1990; RFWP 1955; Stolzer 1955). One study included participants who were not randomly assigned and was at high risk of bias (Massell 1961) (Figure 1; Figure 2).

Figure 1. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Allocation concealment We assessed five studies as having low risk of allocation concealment bias (CRFSG 1960; CRFSG 1965; Dorfman 1961; Haffejee 1990; RFWP 1955), two as having unclear risk (Stolzer 1955; Voss 2001) and one as having high risk (Massell 1961) (Figure 1; Figure 2).

1961) of participants withdrew from the studies, died or were lost to follow-up. We determined that four studies were at low risk of incomplete outcome bias (RFWP 1955; Haffejee 1990; Massell 1961; Stolzer 1955). One study had unclear risk of bias (Voss 2001), two were at high risk because participants were not analysed in the groups to which they were randomly assigned (CRFSG 1960; CRFSG 1965) and one study was at high risk because 16% of participants were lost (Dorfman 1961).

Blinding of participants and personnel Blinding of study participants was clearly described in only three studies (Haffejee 1990; Voss 2001; CRFSG 1965); two studies used a double-blind design (Haffejee 1990; Voss 2001) and were considered to be at low risk of bias. The third study, CRFSG 1965, used both a single-blind and and a double-blind design and was labelled as having a high risk of bias. Three studies had unclear risk of bias (CRFSG 1960; RFWP 1955; Stolzer 1955). Three studies were at high risk of bias: One used a consecutive single- and double-blind study group (CRFSG 1965). One study (Dorfman 1961) specified that it was difficult for observers in this study to be unaware of group assignments because of the striking effects of corticosteroid therapy, and one included participants for which no blinding was applied (Massell 1961) (Figure 1; Figure 2). Three studies had low risk of detection bias (Haffejee 1990; Stolzer 1955; Voss 2001), two had unclear risk of detection bias (CRFSG 1960; RFWP 1955) and three had high risk of detection bias (CRFSG 1965; Dorfman 1961; Massell 1961) (Figure 1; Figure 2).

Selective reporting Most studies did not report outcomes in the Methods and therefore were at unclear risk of reporting bias (CRFSG 1960; CRFSG 1965; Dorfman 1961; Haffejee 1990; Massell 1961; RFWP 1955). One study was at low risk (Stolzer 1955), and one was at high risk (Voss 2001) (Figure 1; Figure 2). Overall risk of bias in most studies was high or unclear for all biases except allocation concealment and incomplete outcome bias, and most studies had unclear or high risk of bias for most types of bias.

Effects of interventions We identified eight randomised controlled trials with dichotomous data describing cardiac outcomes in participants given antiinflammatory agents. All studies examined cardiac outcomes after at least one year. None of the studies undertook an intention-totreat analysis or compared aspirin versus placebo.

Primary outcome - cardiac disease after one year Incomplete outcome data No intention-to-treat analysis was undertaken in any of the trials, despite small numbers of participants ’crossing over’ to other treatment groups within trials (CRFSG 1960; CRFSG 1965). Three participants in the carditis group in the CRFSG 1965 trial were changed from the acetylsalicylic acid (aspirin) to prednisone treatment. Four participants were moved from the aspirin group to the prednisone group in CRFSG 1960. One participant was initially randomly assigned to the aspirin group and then was changed to the prednisone group because he was critically ill. Three others were changed to prednisone because they had a poor response to aspirin. One of these participants subsequently died. In RFWP 1955, five participants were moved from the aspirin group to other treatment groups (three to ACTH, two to cortisone) because of severe illness. Of these, four participants were included for analysis under their original randomisation group (aspirin), and the other was excluded from the final analysis. Withdrawal of participants or loss to follow-up was well described in all studies. Between 3.2% (Voss 2001) and 16% (Dorfman

Corticosteroids versus aspirin

Significant statistical heterogeneity was observed between trials (I 2 = 69%, χ 2 = 16.04, df = 5, P value = 0.0062; Analysis 1.1). Antiinflammatory agents studied included ACTH (corticotrophin), cortisone, dexamethasone, prednisone and aspirin. Pooled analysis showed no evidence of differences between steroidal agents and aspirin in preventing cardiac outcomes (RR 0.87, 95% CI 0.66 to 1.15; Analysis 1.1). Three studies showed some benefit of steroids over aspirin (Dorfman 1961; Massell 1961; Stolzer 1955), with only one (Dorfman 1961) showing statistical significance (RR 0.43, 95% CI 0.19 to 0.97). Three studies showed higher risk of cardiac disease at one year after treatment with corticosteroids compared with aspirin (CRFSG 1960; CRFSG 1965; RFWP 1955). One study stood out as the only study displaying some advantage for aspirin, although statistically insignificant, in reducing risk of cardiac disease compared with prednisone (RR 1.71, 95% CI 0.92 to 3.19) (CRFSG 1960).

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Hydrocortisone versus aspirin Dorfman 1961 was the sole randomised trial comparing oral hydrocortisone versus aspirin. A significant reduction in cardiac disease was reported at one year when hydrocortisone was compared with aspirin (RR 0.43, 95% CI 0.19 to 0.97). Although cardiac disease was significantly reduced with hydrocortisone, no significant difference between various treatment groups (hydrocortisone, aspirin, hydrocortisone and aspirin and no treatment) was observed in the development of new murmurs among participants with murmurs absent at the start of the study. Prednisone versus aspirin We used in this analysis data from two studies (CRFSG 1960; CRFSG 1965) with 212 participants. The pooled estimate showed no reduction in heart disease after one year when prednisone was used over aspirin (RR 1.13, 95% CI 0.52 to 2.45; Analysis 2.1). Outcomes of participants with severe disease Only five studies reported outcomes in participants with severe disease characterised by a grade 3 apical systolic murmur assessed clinically (CRFSG 1960; Dorfman 1961; Haffejee 1990; RFWP 1955; Voss 2001) or by use of echocardiographic criteria (Voss 2001) at the start of treatment. The number of participants with severe heart disease was small compared with the total number of participants. No evidence suggested a difference in reduction in heart disease after one year between corticosteroids and aspirin (three studies, 119 participants, RR 0.94, 95% CI 0.32 to 2.70; Analysis 1.2). Participants with severe heart disease in the CRFSG 1960 study failed to improve with prednisone or aspirin (risk ratio therefore was not estimable). One study in which only nine participants had severe disease showed hydrocortisone to be more beneficial in reducing the severity of cardiac disease compared with aspirin after one year (RR 0.17, 95% CI 0.03 to 1.00) (Dorfman 1961). The study with the greatest number of participants with severe disease (n = 89) found no statistically significant benefit for corticosteroid therapy compared with aspirin (RR 2.16, 95% Cl 0.97 to 4.81) (RFWP 1955).

similar to those of placebo for participants with severe valvular disease (Haffejee 1990; Voss 2001). Secondary outcomes Outcomes such as reduction in hospital stay, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were not reported by CRFSG 1960 and Massell 1961. CRFSG 1965 reported similar ESR levels in the prednisone and salicylate groups. Dorfman 1961 graphically depicted a prompt and striking drop in ESR with the use of hydrocortisone, which increased upon withdrawal of therapy. Aspirin also had a striking effect on ESR, but not as marked as that of hydrocortisone. Haffejee 1990 found ESR, CRP and sleeping pulse responses to be similar in prednisone and placebo groups. RFWP 1955 showed a more dramatic drop in ESR in the corticosteroid groups compared with the aspirin groups, but this increased sharply, although temporarily, in both corticosteroid groups after treatment was stopped, in contrast to a negligible change in the aspirin group. ESR eventually reached a similarly low level in all three groups at 13 weeks, and this level was maintained at one year. Corticotrophin had the most marked effect on reducing ESR compared with cortisone and aspirin in the Stolzer 1955 trial. Voss 2001 demonstrated that ESR measurements in the IVIG and placebo groups were similar at six weeks following the intervention. However, a significant difference was noted at one week and two weeks, with ESR significantly higher in the IVIG group. Adverse effects of study drugs Complications related to trial medication were not disclosed in five studies (CRFSG 1960; CRFSG 1965; Haffejee 1990; Stolzer 1955; Voss 2001). Untoward reactions were reported in the remaining three trials. Massell 1961 noted steroidal effects such as weight gain, moon face, buffalo hump, striae of the skin and acne. RFWP 1955 found that ACTH and cortisone groups had similar steroidal effects. Participants in the aspirin group experienced tinnitus, deafness, nausea and hyperventilation. Dorfman 1961 reported symptoms of nausea, emesis and tinnitus in some participants receiving aspirin. Two participants receiving hydrocortisone and aspirin developed gastric ulceration.

Prednisone and intravenous immunoglobulin (IVIG) versus placebo

Effects of the two study medications were assessed separately. The benefit of using IVIG (Voss 2001) (RR 0.87, 95% CI 0.55 to 1.39) or prednisone (Haffejee 1990) (RR 1.78, 95% CI 0.95 to 3.34) over placebo to prevent cardiac disease in patients with acute rheumatic fever was not statistically significant. Outcome of severe disease Two studies confirmed that the effects of prednisone (RR 2.5, 95% Cl 0.42 to 14.83) or IVIG (RR 0.79, 95% Cl 0.31 to 1.96) were

Concomitant therapy Concomitant treatments were very similar in these trials. Bed rest, penicillin for 10 days, prophylactic antibiotics after 10 days, diuretics and digitalis (for heart failure) constituted standard auxiliary therapy in five studies (Dorfman 1961; Haffejee 1990; RFWP 1955; Stolzer 1955; Voss 2001). Bed rest may be an important co-factor in the success of corticosteroid therapy. Although penicillin prophylaxis was provided in the CRFSG 1960 study, bed rest was not reported as part of the treatment regimen. Supplementary treatment was not indicated by CRFSG 1965 and Massell 1961.

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DISCUSSION

Summary of main results None of the included trials showed consistent benefit with the use of corticosteroids, aspirin or IVIG in ameliorating or avoiding cardiac disease one year after treatment among participants with acute rheumatic fever. The combined analysis of corticosteroid agents ACTH, cortisone, prednisone, dexamethasone and hydrocortisone indicated a weak overall favourable outcome in preventing cardiac disease compared with aspirin (random risk ratio 0.87, 95% confidence interval 0.66 to 1.15). Thus, the data do not provide sufficient quantitative evidence to support the use of corticosteroid therapy, IVIG or aspirin to prevent cardiac disease in patients with acute rheumatic fever, if they offer no compelling reason for selection of corticosteroids over aspirin or vice versa.

Overall completeness and applicability of evidence Both studies comparing anti-inflammatory agents, oral prednisone and IVIG versus placebo identified no benefit from the use of active agents (Haffejee 1990; Voss 2001). Two smaller studies (Dorfman 1961; Stolzer 1955) stood out because they confirmed benefit derived from the use of oral hydrocortisone and intramuscular cortisone, respectively, in preventing cardiac disease compared with aspirin. However, in the light of the absence of evidence of efficacy of aspirin (no trial comparing aspirin with placebo), the significance of these results is unknown.

Quality of the evidence Type, dose and duration of corticosteroids and other medications varied between studies. Differences in outcomes between prednisone and hydrocortisone may be explained by the fact that prednisone is a less effective agent than hydrocortisone, or that corticosteroids need to be given for a longer period (12 weeks) to be effective, as was the case in the Dorfman 1961 study. In at least three of the trials (CRFSG 1960; CRFSG 1965; RFWP 1955), participants ’crossed over’ from one intervention to another. However, the meta-analysis was performed by using the original randomisation groups in an attempt to adhere to ’intention-to-treat’ principles. Only five studies included participants with severe cardiac disease and documented outcomes following treatment with steroidal agents, IVIG or aspirin. Overall 152 participants were included in this subanalysis of only data from Dorfman 1961, and the fewest participants (n = 9) showed a statistical beneficial outcome following administration of oral hydrocortisone. The inclusion criteria of Dorfman 1961 did not include carditis, but methods of

selection and assignment of cases appear to have resulted in satisfactory random assignment of participants with carditis to each group. Other severe outcomes such as death and the requirement for heart surgery were reported in only three studies (CRFSG 1960; Haffejee 1990; RFWP 1955). Investigators reported a total of eight deaths and five participants requiring surgery, with five deaths and four surgical interventions occurring in the corticosteroid group. The data refute a life-saving role for corticosteroid therapy in patients with rheumatic carditis. Secondary objectives of this review were to evaluate the effects of anti-inflammatory treatment on hospital stay and on erythrocyte sedimentation rate and C-reactive protein values. Reporting of these outcomes was too varied and inconsistent for adequate analysis. Corticosteroids appeared superior to aspirin in the rate at which ESR drops. However, this is not a compelling reason to choose one drug over another, as the significance of this rapid fall is not defined. Five studies did not report on adverse events. The three studies that did so noted steroidal effects such as weight gain, moon face, buffalo hump, striae of the skin and acne and gastric ulceration. Participants in the aspirin group experienced tinnitus, deafness, nausea and hyperventilation.

Potential biases in the review process Limitations of the review process and potential sources of bias in this review include lack of intention-to-treat analyses in the original studies, along with antiquated studies and the small number of trials available for analysis. Statistical heterogeneity between studies was significant. Major differences between studies were noted regarding patient diagnosis, inclusion criteria, interventions (various types, doses used, duration), outcomes (mainly type of outcome, such as systolic murmurs, diastolic murmurs and “carditis”) and methodology, such as lack of blinding in some studies. For all these reasons, results should be interpreted with caution.

Agreements and disagreements with other studies or reviews Prednisone continues to be recommended in contemporary reference textbooks for patients with carditis and acute rheumatic fever (Ayoub 1995; El-Said 1998). The recommended duration of steroid treatment differs from that used in the studies mentioned above, for example, Ayoub 1995 suggests 2 mg/kg/d of prednisone for two weeks followed by gradual withdrawal over the following two weeks, and El-Said 1998 recommends 2 mg/kg/d of prednisone or prednisolone for three to four weeks. In addition, Ayoub 1995 suggests that aspirin should be used in patients with carditis for four to eight weeks at a dose of 90 to 100 mg/kg/d, depending on clinical response. A more recent review (Kumar 2013) indicates that no significant change has been reported in the management

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of acute rheumatic fever over the past 50 years, and suggests that anti-inflammatory agents such as aspirin and steroids, although they continue to be used to control rheumatic activity, do not cure rheumatic fever. The evidence base for these recommendations is clearly lacking. Rheumatic fever and its valvular heart disease sequelae continue to be major causes of acquired heart disease in developing countries. Despite this, only one study was carried out in a developing country (Haffejee 1990), and the remaining seven studies took place in the USA, the United Kingdom and New Zealand. The number of randomised controlled trials examining treatment of acute rheumatic fever has diminished since the 1950s and 1960s in tandem with the decrease in prevalence of rheumatic heart disease in developed countries. The relevance and applicability to the current situation of data derived from studies performed 35 to 50 years ago in poorer countries remain pertinent because of the high incidence of rheumatic fever reported in industrialised countries during that period (Olivier 2000).

AUTHORS’ CONCLUSIONS Implications for practice Up to now, no evidence provided by the reviewed studies has supported the benefit of using anti-inflammatory drugs such as corticosteroids, intravenous immunoglobulins or aspirin to prevent or reduce cardiac disease in patients presenting with acute rheumatic fever. However, all findings should be interpreted cautiously, as

most studies were conducted over 40 years ago and have considerable risk of bias.

Implications for research Available studies have not established the efficacy of corticosteroids, intravenous immunoglobulins and aspirin. No published randomised controlled trials have examined anti-inflammatory treatment for acute rheumatic fever since 2001 (Voss 2001). Therefore a randomised controlled trial must be undertaken to compare aspirin and other non-steroidal anti-inflammatory agents versus placebo. Once the effectiveness of aspirin has been established, comparison with corticosteroids becomes relevant. Further randomised placebo-controlled trials examining the more commonly used corticosteroids (e.g. prednisone, intravenous methylprednisolone) are warranted to establish whether any net benefit is obtained when these drugs are used. The availability and use of echocardiography and other newer technologies in future randomised controlled trials will assist greatly in providing more precise, valid and objective assessment of changes in cardiac lesions.

ACKNOWLEDGEMENTS The review authors would like to thank Juliet Manyemba for her contribution to previous versions of the reviews, for her appraisal of the quality of papers, assisting with abstraction of data from papers, analyses and interpretation of data and also providing a methodologic perspective and general advice. In addition, the authors would like to thank the editors and co-ordinators of the Cochrane Heart Group for assistance provided.

REFERENCES

References to studies included in this review CRFSG 1960 {published data only} Combined Rheumatic Fever Study Group. New York City, Baltimore, Boston, Cleveland. A comparison of the effect of prednisone and acetylsalicylic acid on the incidence of residual rheumatic heart disease. New England Journal of Medicine 1960;262:895–902. CRFSG 1965 {published data only} Combined Rheumatic Fever Study Group. Baltimore and New York City. A comparison of short-term, intensive prednisone and acetylsalicylic acid therapy in the treatment of acute rheumatic fever. New England Journal of Medicine 1965;272:63–70. Dorfman 1961 {published data only} Dorfman A, Gross JI, Lorincz AE. The treatment of acute rheumatic fever. Pediatrics 1961;27:692–706.

Haffejee 1990 {published data only} Haffejee IE, Moosa A. A double-blind placebo-controlled trial of prednisone in active rheumatic carditis. Annals of Tropical Paediatrics 1990;10:395–400. Massell 1961 {published data only} Massell BF, Jhaveri S, Czoniczer G, Barnet R. Treatment of rheumatic fever and rheumatic carditis. observations providing a basis for the selection of aspirin or adrenocortical steroids. Medical Clinics of North America 1961;45: 1349–68. RFWP 1955 {published data only} A joint report by the Rheumatic Fever Working Party of the Medical Research Council of Great Britain and the Subcommittee of Principal Investigators of the American Council on Rheumatic Fever and Congenital Heart Disease, American Heart Association. The treatment of acute rheumatic fever in children. A cooperative clinical trial of ACTH, cortisone and aspirin. Circulation 1955;11:343–71.

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Stolzer 1955 {published data only} Stolzer BL, Houser HB, Clark EJ. Therapeutic agents in rheumatic carditis. Comparative effects of acetylsalicylic acid, corticotrophin, and cortisone. Archives of Internal Medicine 1955;95:677–88. Voss 2001 {published data only} Voss LM, Wilson NJ, Neutze JM, Whitlock RML, Ameratunga RV, Cairns LM, et al. A randomized controlled trial of intravenous immunoglobulin in acute rheumatic fever. Circulation 2001;103(3):401–6.

References to studies excluded from this review Akcoral 1996 {published data only} Akcoral A, Oran B, Tavli V, Nurettin U, Cevik NT. Effects of high-dose intravenous methylprednisolone in children with acute rheumatic fever. Acta Paediatrica Japonica 1996; 38:28–31. Bywaters 1956 {published data only} Bywaters EGL. Treatment of rheumatic fever. Circulation 1956;14:1153–8. Bywaters 1961 {published data only} Bywaters EGL, Thomas GT. Bed rest, salicylates and steroids in rheumatic fever. British Medical Journal 1961;1: 1628–34. Camara 2002 {published data only} Camara EJN, Braga JCV, Alves-Silva LS, Camara GF, da Silva Lopes AA. Comparison of an intravenous pulse of methylprednisolone versus oral corticosteroid in severe acute rheumatic carditis: a randomized clinical trial. Cardiology in the Young 2002;12:119–24. Couto 1987 {published data only} Couto AA, de Oliveira GM, Campos AL, Alves ML, Mansur EM, Pareto Junior RC, et al. Duration of rheumatic activity in patients treated with oral corticoids vs. pulse therapy [Duracao da atividade reumatica em pacientes tratados com corticoide oral vs. pulsoterapia]. Arquivos Brasileiros de Cardiologia 1987;48(6):371–3. Czoniczer 1964 {published data only} Czoniczer G, Amezcua F, Pelargonio S, Massell B. Therapy of severe rheumatic carditis; comparison of adrenocortical steroids and aspirin. Circulation 1963;29:813–9. Done 1955 {published data only} Done AK, Ely RS, Ainger LE, Rodman S, Kelley VC. Therapy of acute rheumatic fever. Pediatrics 1955;15: 522–36. Ferencz 1959 {published data only} Ferencz C, Markowitz M, Bunin J. The effect of large doses of prednisone on acute rheumatic fever. American Journal of Diseases in Childhood 1959;97:561–70. Friedman 1962 {published data only} Friedman S, Harris TN, Caddell JL. Long-term effects of ACTH and cortisone therapy in rheumatic fever. The Journal of Pediatrics 1962;60:55–61. Hashkes 2003 {published data only} Hashkes PJ, Tauber T, Somekh E, Brik R, Barash J, Mukamel M, et al. Naproxen as an alternative to aspirin for

the treatment of arthritis of rheumatic fever: a randomized trial. The Journal of Pediatrics 2003;143:399–410. Herdy 1993 {published data only} Herdy GV, Couto AA, Fernandes JC, de Olivaes MC, Berger R, Elias VE. Pulse therapy (high doses of venous methylprednisolone) in children with rheumatic carditis. Prospective study of 40 episodes. Arquivos Brasileiros de Cardiologia 1993;60(6):377–88. Herdy 1999 {published data only} Herdy GVH, Pinto CA, Olivaes MC, Carvalho EA, Tchou Hsu, Cosendey R, et al. Rheumatic carditis treated with high doses of pulse therapy methylprednisolone. Results in 70 children over 12 years [Cardite Reumatica Trada comAltas Doses de Metilprednisolona Venosa (Pulsoterapia). Resultados em 70 Criancas Durante 12 Anos]. Arq Bras Cardiol 1999;72(5):601–3. Herdy 2012 {published data only} Herdy GVH, Gomes RS, Silva AEA, Silva LS, Lopes VGS. Follow-up of rheumatic carditis treated with steroids. Cardiology in the Young 2012;22:263–9. Human 1984 {published data only} Human DG, Hill ID, Fraser CB. Treatment choice in acute rheumatic carditis. Archives of Disease in Childhood 1984; 59:410–3. Marshall 1989 {published data only} Marshall RL. Ibuprofen and aspirin in acute rheumatic fever. Journal of the American Medical Association 1989;263 (12):1633–4. McCue 1957 {published data only} McCue CM. Steroid therapy for rheumatic fever. Journal of Pediatrics 1957;51:255–61. Morino 1973 {published data only} Morino F, Possati F, Santarelli P, Paolini E, Calafiore AM. Use of ibuprofen in the control of rheumatic activity [L’impiego dell’ibuprofen nel controllo dell’attivita reumatica]. Minerva Medica 1973;64(47):2475–8. Naik 2002 {published data only} Naik N, Bahl VK. Acute rheumatic fever: whither steroids?. Indian Heart Journal 2002;54:363–7. Narin 2003 {published data only} Narin N, Karakukcu M, Narin F, Akcakus M, Erez R, Halici C. Is pentoxifylline therapy effective for the treatment of acute rheumatic carditis?. Journal of Paediatrics and Child Health 2003;39(3):214–8. Okuni 1975 {published data only} Okuni M, Fujikawa S. Effect of steroid hormone on rheumatic carditis. Japanese Heart Journal 1976;17(5): 545–9. Paz 2006 {published data only} Paz JA, Silva CAA, Marques-Dias MJ. Randomized doubleblind study with prednisone in Sydenham’s chorea. Pediatric Neurology 2006;34:264–9.

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Rowe 1953 {published data only} Rowe RD, McKelvey AD, Keith JD. The use of ACTH, cortisone and salicylates in the treatment of acute rheumatic fever. Canadian Medical Association Journal 1953;68:15–20. Singh 1998 {published data only} Singh S. Aspirin in acute rheumatic fever. Indian Pediatrics 1998;35(11):1159–60. Uziel 2000 {published data only} Uziel Y, Hashkes PJ, Kassem E, Padeh S, Goldman R, Vollach B. The use of naproxen in the treatment of children with rheumatic fever. The Journal of Pediatrics 2000;137(2): 269–71. Wilson 1953 {published data only} Wilson MG, Helper HN, Lubschez R, Hain K, Epstein N. Effect of short-term administration of corticotropin in active rheumatic carditis. American Journal of Diseases in Childhood 1953;86:131–46. Wilson 1959 {published data only} Wilson MG, Lim WL. Short-term hormone therapy; its effect in active rheumatic carditis of varying duration. New England Journal of Medicine 1959;260:802–7.

Additional references Abraham 1991 Abraham MT, Cherian G. Cardiology. In: Chatterjee K editor(s). An Illustrated Text/Reference. New York: Gower Medical Publishing, 1991:10.98–10.116. AHA 1965 American Heart Association Committee to Revise the Jones’ Criteria. Jones’ criteria (revised) for guidance in the diagnosis of rheumatic fever. Circulation 1965;32:664. Ayoub 1995 Ayoub EM. Acute rheumatic fever. In: Emmanouilides GC, Riemenschneider TA, Allen HD, Gutgesell HP editor (s). Moss and Adams’ Heart Disease in Infants, Children, and Adolescents: Including the Fetus and the Young Adult. 5th Edition. Baltimore: Williams and Wilkinson, 1995: 1400–16. Barlow 1990 Barlow JB, Marcus RH, Pocock WA, Barlow CW, Essop R, Sareli P. Mechanisms and management of heart failure in active rheumatic carditis. South African Medical Journal 1990;78:181–6. Barrett 1984 Barrett DJ. Pathogenesis of acute rheumatic fever. In: Majeed HA, Yousof AM editor(s). Research on Cardiac and Renal Sequelae of Streptococcal Infections. MunichDeisenhofen: Dustri-Verlag, 1984:32–48. Dajani 1992 Dajani AS, Ayoub E, Bierman FZ, Bisno AL, Denny FW, Durack DT, et al. Guidelines for the diagnosis of rheumatic fever: Jones criteria, updated 1992. Journal of the American Medical Association 1992;268:2069–73.

DiSciascia 1980 DiSciascia G, Taranta A. Rheumatic fever in children. American Heart Journal 1980;99:635–58. El-Said 1998 El-Said GM, El-Refaee MM, Sorour KA, El-Said HG. Rheumatic fever and rheumatic heart disease. In: Garson A, Bricker JT, Fischer DJ, Neish SR editor(s). The Science and Practice of Pediatric Cardiology. 2nd Edition. Baltimore: Williams and Wilkins, 1998:1691–724. Ganguly 1992 Ganguly NK, Anand IS, Koicha M, Jindal S, Wahi PL. Frequency of D8/17 B lymphocyte alloantigen in north Indian patients with rheumatic heart disease. Immunology and Cell Biology 1992;70:9–14. Global Burden 2013 Zuhlke LJ, Steer AC. Estimates of the global burden of rheumatic heart disease. Global Heart 2013;8(3):189–95. Guilherme 1991 Guilherme L, Weidebach W, Kiss MH, Snitcowsky R, Kalil J. Association of human leukocyte class II antigens with rheumatic fever or rheumatic heart disease in Brazilian population. Circulation 1991;83:1995–8. Halim 1961 Halim AM, Jacques JE. Rheumatic heart disease in the Sudan. British Heart Journal 1961;23:383. Herdy 1992 Herdy GV, Zabriskie JB, Chapman F, Khanna A, Swedo S. A rapid test for the detection of a B-cell marker (D8/17) in rheumatic fever patients. Brazilian Journal of Medical and Biological Research 1992;25(8):789–94. Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1 [updated March 2011]. The Cochrane Collaboration. www.cochrane-handbook.org, 2011. Jones 1944 Jones TD. The diagnosis of rheumatic fever. Journal of the American Medical Association 1944;126:481–6. Kaplan 1963 Kaplan MH, Suchy ML. Immunologic relation of streptococcal and tissue antigens: I. Properties of an antigen in certain strains of group A streptococci exhibiting an immunologic cross reaction with human heart tissue. Journal of Immunology 1963;90:595. Kaplan 1964 Kaplan MH, Bolande R, Rakita L, Blair J. Presence of bound immunoglobulin and complement in the myocardium in acute rheumatic fever. Association with cardiac failure. New England Journal of Medicine 1964;271:637–45. Khanna 1989 Khanna AK, Buskirk DR, Williams RC, Gibofsky A, Crow MK, Menon A, et al. Presence of non-HLA B cell antigen in rheumatic fever patients and their families as defined by a monoclonal antibody. Journal of Clinical Investigations 1989;83(5):1710–6.

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Kingsley 1987 Kingsley RH, Pocock WA. Rheumatic fever and rheumatic heart disease. In: Barlow JB editor(s). Perspectives on the Mitral Valve. Philadelphia: FA Davis, 1987:227–45. Kumar 2013 Kumar RK, Tandon R. Rheumatic fever and rheumatic heart disease: the last 50 years. Indian Journal of Medical Research 2013;137:643–58. Lefebvre 2011 Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. Cochrane Collaboration, 2011. Markowitz 1972 Markowitz M, Gordis L. Rheumatic Fever. 2nd Edition. Philadelphia: WB Saunders, 1972. Massell 1988 Massell BF, Chute CG, Walker AM, Kurland GS. Penicillin and the marked decrease in morbidity and mortality from rheumatic fever in the United States. New England Journal of Medicine 1988;318:280–6. McLaren 1975 McLaren MJ, Hawkins DM, Koornhof HJ, Bloom KR, Bramwell-Jones DM, Cohen E, et al. Epidemiology of rheumatic heart disease in black children of Soweto, Johannesburg. British Medical Journal 1975;2:474–7. Olivier 2000 Olivier C. Rheumatic fever - is it still a problem?. Journal of Antimicrobial Chemotherapy 2000;45(Suppl 13):13–21. Olmez 1993 Olmez U, Turgay M, Ozenirler S, Tutkak H, Duzqun N, Duman M, et al. Association of HLA class I and II antigens with rheumatic fever in Turkish population. Scandinavian Journal of Rheumatology 1993;2:49–52. Padmavati 1978 Padmavati S. Rheumatic fever and rheumatic heart disease in developing countries. Bulletin of the World Health Organization 1978;56:543. Shiffman 1995 Shiffman RN. Guideline maintenance and revision: 50 years of the Jones criteria for diagnosis of rheumatic fever. Archives of Pedatric and Adolescent Medicine 1995;149: 727–32.

Siegel 1961 Siegel AC, Johnson EE, Stollerman GH. Controlled studies of streptococcal pharyngitis in a paediatric population. 1. Factors related to the attack rate of rheumatic fever. New England Journal of Medicine 1961;265:559–65. Taranta 1964 Taranta A. Rheumatic fever in children and adolescents: a long-term epidemiologic study of subsequent prophylaxis, streptococcal infections and clinical sequelae: IV. Relation of rheumatic fever recurrence rate per streptococcal infection to the titers of streptococcal antibodies. Annals of Internal Medicine 1964;60 (Suppl 5):47. Veasy 1987 Veasy LG, Wiedmeier SE, Orsmond GS, Ruttenberg HD, Boucek MM, Roth SJ, et al. Resurgence of acute rheumatic fever in the intermountain area of the United States. New England Journal of Medicine 1987;316(8):421–7. WHO/ISCF 1995 WHO/ISCF. Strategy for controlling rheumatic fever/ rheumatic heart disease with emphasis on prevention: memorandum from a joint WHO/ISFC meeting. Bulletin of the World Health Organization 1995;73:583–7. Williams 1982 Williams RC Jr, Raizada V, Prakash K, van de Rijn I, Zabriskie JB, Stobo JD, et al. Changes in T lymphocyte subsets during acute rheumatic fever. Journal of Clinical Immunology 1982;3:166–72. Yegin 1997 Yegin O, Coskun M, Ertug H. Cytokines in acute rheumatic fever. European Journal of Pediatrics 1997;156:25–9.

References to other published versions of this review Cilliers 2003 Cilliers A, Manyemba J, Saloojee H. Anti-inflammatory treatment for carditis in acute rheumatic fever. Cochrane Database of Systematic Reviews 2003, Issue 2. [DOI: 10.1002/14651858.CD003176] Cilliers 2012 Cilliers A, Manyemba J, Adler AJ, Saloojee H. Antiinflammatory treatment for carditis in acute rheumatic fever. Cochrane Database of Systematic Reviews 2012, Issue 6. [DOI: 10.1002/14651858.CD003176.pub2] ∗ Indicates the major publication for the study

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CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID] CRFSG 1960 Methods

DESIGN - Prospective - Parallel with cross-over of 4 participants from ASA to prednisone ALLOCATION - Random - Controlled BLINDING - Nil WITHDRAWALS - 2 described

Participants

INCLUSION CRITERIA - First attack of rheumatic fever, moderate to severe carditis (pericarditis, cardiomegaly, cardiac failure, apical systolic murmur and apical/aortic diastolic murmurs), < 12 years of age - Diagnosis of acute rheumatic fever according to Jones criteria not indicated - Time to treatment within 28 days RANDOMISED (N = 57) - Prednisone = 33 (29 originally, 4 added from ASA group): Analysis was done in the groups to which participants were originally randomly assigned - ASA = 24 (28 originally, 4 changed to prednisone group) 2 PARTICIPANT GROUPS AT START OF TREATMENT • NORMAL HEARTS ◦ Prednisone = 12, ASA = 16 • HEART DISEASE ◦ Prednisone = 16 + 4, ASA = 7 ⋄ 11 participants in ASA group initially; 4 changed to prednisone group GRADE 3 APICAL SYSTOLIC MURMURS AT START - Prednisone = 12 - Acetylsalicylic acid = 6 WITHDRAWALS - 1 participant died (participant started on ASA and changed to prednisone) - 1 lost to 1-year follow-up = Prednisone group AGE (average in years) - Prednisone = 8.6 - Aspirin = 8.3 SEX (M:F) - Prednisone = 15:13 - Aspirin = 13:14

Interventions

TEST GROUP - Prednisone 60 mg/d × 3 wk, then gradually reduced over 9 wk - Followed by 3 wk of observation - Total dose = 3 g

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CRFSG 1960

(Continued)

CONTROL - Acetylsalicylic acid (ASA) ◦ 50 mg/lb/d × 9 wk, 30 mg/lb/d × 2 wk, then ◦ 15 mg/lb/d × 1 wk, followed by 3 wk of observation CO-TREATMENT - Penicillin × 10 d - Prophylactic regimen after 10 d - Acetylsalicylic acid × 24 h in febrile participants to allow more accurate assessment of cardiac murmurs before admission to the study Outcomes

ANALYSIS - Intention-to-treat - Not specified PARTICIPANTS WITH CARDIAC MURMURS 1 YEAR - Prednisone = 16/28 • Mitral incompetence (MI) = 13 • Aortic incompetence (AI) = 3 - ASA = 9/27 • MI = 8 • AI = 1 GRADE 3 MURMURS AT I YEAR - Prednisone = 12/12 - ASA = 9/9 (includes 1 death) OTHER OUTCOMES - Not included in the study

Notes

- Full-text paper - Supported by grant from the National Institutes of Health, US Public Health Service, Bethesda, in part by the Minnie and Benjamin Landsberg Memorial Foundation, Baltimore, and by the Heart Association of Maryland and the Schering Corporation, Bloomfield, New Jersey

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Unclear risk bias)

Not reported

Allocation concealment (selection bias)

Quote: “Each of the 8 hospitals was given a series of sealed envelopes prepared by the Department of Medical Statistics, New York University, which determined whether the patient should receive prednisone or acetylsalicylic acid”

Low risk

Blinding of participants and personnel Unclear risk (performance bias) All outcomes Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Not reported

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CRFSG 1960

(Continued)

Blinding of outcome assessment (detection Unclear risk bias) All outcomes

Not reported

Incomplete outcome data (attrition bias) All outcomes

High risk

4 participants who switched from aspirin to prednisone were analysed separately, not as aspirin

Selective reporting (reporting bias)

Unclear risk

Outcomes not clearly outlined in Methods, so difficult to assess

CRFSG 1965 Methods

DESIGN - Prospective - Parallel with cross-over of 3 participants from ASA to prednisone ALLOCATION - Random - Controlled BLINDING - Single-blind (SB) for 2 years (both carditis and polyarthritis groups) - Double-blind (DB) for 2 years (carditis group only) WITHDRAWALS - 6 described

Participants

INCLUSION CRITERIA - First episode of rheumatic fever, randomly assigned according to presence of carditis or polyarthritis - Carditis included finding of congestive cardiac failure, pericarditis, cardiac enlargement, significant apical systolic murmurs and aortic diastolic murmurs = All analysed together as “carditis” - Diagnosis of acute rheumatic fever according to Jones criteria not indicated - Time to treatment not indicated RANDOMISED (N = 160) SINGLE-BLIND (SB) GROUP CARDITIS - Prednisone = 18 - Acetylsalicylic acid (ASA) = 21 (3 changed to prednisone group; analysis was done in the groups to which they were randomly assigned) POLYARTHRITIS - Prednisone = 45 (12 = carditis) - ASA = 42 (6 = carditis) DOUBLE-BLIND (DB) GROUP CARDITIS - Prednisone = 16 - ASA = 18 GRADE 3 APICAL SYSTOLIC MURMURS AT START - Prednisone = 20

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CRFSG 1965

(Continued)

- ASA = 24 WITHDRAWALS - 3 dropouts in SB polyarthritis group (2 ASA, 1 prednisone) AGE (average in years) CARDITIS GROUP - Prednisone 8.1 - ASA 8.7 POLYARTHRITIS GROUP - Prednisone 9.3 - ASA 9 SEX (M:F) - Not indicated Interventions

TEST GROUP - Prednisone 3 mg/lb for 7 d. Second course if persistent carditis after 1 wk (both carditis and polyarthritis groups) CONTROL GROUP - ASA • Carditis group = 50 mg/lb for 6 wk, then 25 mg/lb for 2 wk • Polyarthritis group = 50 mg/lb for 4 wk (15 patients × 2 y). Later, 50 mg/lb for 1 wk (27 participants) CO-TREATMENT - Not indicated

Outcomes

ANALYSIS - Intention-to-treat - Not specified PATIENTS WITH CARDIAC DISEASE AT 1 YEAR CARDITIS GROUP - Prednisone = 19/34 - ASA = 26/39 POLYARTHRITIS GROUP (3 dropouts) - Prednisone = 1/44 - ASA = 0/40 (not included in review meta-analysis) This analysis combines “single-blind” and “double-blind” groups GRADE 3 APICAL SYSTOLIC MURMURS AT 1 YEAR (SB & DB groups) - No indication given OTHER OUTCOMES - Elevated ESR at 1 wk and at 3 wk POLYARTHRITIS GROUP AFTER 1 WK Prednisone = 22/42 unchanged, 10/42 moderately decreased, 10/42 normal ASA = 26/37 unchanged, 3/37 moderately decreased, 11/37 normal (numbers are incorrect) AFTER 3 WK Prednisone = 15/38 elevated, 23/38 moderately elevated ASA = 19/37 elevated, 18/37 moderately elevated or normal - No difference between prednisone and aspirin groups

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CRFSG 1965

(Continued)

Notes

- Full-text paper - Supported by grants from the National Institutes of Health, US Public Health Service, Bethesda, Maryland

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Unclear risk bias)

Not reported

Allocation concealment (selection bias)

Quote: “Two separate sets of sealed envelopes (prepared by the Department of Medical Statistics, New York University), one for carditis and one for the polyarthritis cases, were given to each of the 7 participating hospitals”

Low risk

Blinding of participants and personnel High risk (performance bias) All outcomes

During first 2 years of study, medication given on single-blind basis and chief investigator moved participants to different groups

Blinding of outcome assessment (detection High risk bias) All outcomes

During first 2 years of study, medication given on single-blind basis and chief investigator moved participants to different groups

Incomplete outcome data (attrition bias) All outcomes

High risk

3 participants who were switched from ASA to prednisone were analysed separately, not as ASA

Selective reporting (reporting bias)

Unclear risk

Outcomes not clearly outlined in Methods, so difficult to assess

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Dorfman 1961 Methods

DESIGN - Prospective - Parallel ALLOCATION - Random - Controlled BLINDING - Single-blind (1 blinded observer) WITHDRAWALS - 18 initially - 2 later lost to follow-up - 1 died

Participants

INCLUSION CRITERIA - First attack of rheumatic fever - Diagnosis of rheumatic fever was as used in previous study (quoted) - Time to treatment less than 18 days - Grading of intensity of murmurs from 1 to 4. Functional murmurs not included RANDOMLY ASSIGNED (N = 131) 4 treatment groups - Hydrocortisone (F) = 32 - Aspirin (A) = 32 - Hydrocortisone + Aspirin (F + A) = 32 - No specific treatment (O) = 35 PARTICIPANTS WITH CARDITIS RANDOMLY ASSIGNED TO EACH GROUP F = 23, A = 19, F + A = 21, O = 22 GRADE 3 MURMURS AT START F = 6, A = 3, F + A = 2, O = 5 WITHDRAWALS Study started with 150 participants - 18 dropouts initially deemed to be unsuitable candidates - 1 participants in the Hydrocortisone + Aspirin (F + A) group died 6 days after admission - 1 participant was lost to 1-year follow-up (not clear which group the participant was in) AGE (average in years) - Hydrocortisone = 10.0 - Aspirin = 10.2 - Hydrocortisone + Aspirin = 10.7 - No treatment = 10.1 SEX (M:F) - Hydrocortisone = 18:14 - Aspirin = 17:15 - Hydrocortisone + Aspirin = 22:10 - No treatment = 18:17

Interventions

TEST GROUP - Hydrocortisone orally • Participants weighing > 80 lb received 250 mg/d × 96 h

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Dorfman 1961

(Continued)

◦ Then 100 mg/d × 8 wk • Participants weighing < 80 lb received 200 mg/d × 96 h ◦ Then 80 mg/d × 8 wk • Medication was decreased in stepwise fashion from 9 to 12 wk • All participants developed cushingoid facies CONTROL GROUP - Aspirin 3/4 grain/lb for 9 wk, then decreased in stepwise fashion from 10 to 12 wk (to maintain blood level 20 to 30 mg/100 mL) CO-TREATMENT - Digitalis, diuretics, oxygen as required - Bed rest × 15 wk - Procaine Penicillin G on alternate days × 5 d - Maintenance sulfadiazine bid - Potassium chloride - Low-sodium chloride diet Outcomes

ANALYSIS - Intention-to-treat - Not specified PATIENTS WITH CARDITIS AT 1 YEAR (patients with apical systolic murmurs, apical diastolic murmurs and basal diastolic murmurs were analysed separately) APICAL SYSTOLIC - Group F = 4/32 - Group A = 11/32 - Group F + A = 5/31 - Group O = 13/35 APICAL DIASTOLIC - Group F = 1/32 - Group A = 1/32 - Group A + F = 0/31 - Group O = 0/35 BASAL DIASTOLIC - Group F = 1/32 - Group A = 2/32 - Group F + A = 1/31 - Group 0 = 3/35 GRADE 3 MURMURS AT 1 YEAR F = 1/6, A = 3/3, F + A = 0/2, O = 4/5 DEVELOPMENT OF MURMURS IN PARTICIPANTS WITH NO PREVIOUS MURMURS AFTER 1 YEAR - Group F = 0/9 - Group A = 1/13 - Group F + A = 0/11 - Group O = 0/13 OTHER OUTCOMES EFFECT OF TREATMENT ON THE FOLLOWING PARAMETERS - No numbers given. Generalisations and graphs provided • Fever = More rapid drop in hormone-treated groups

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Dorfman 1961

(Continued)

• Pulse rate during sleep = No differences between groups • Polyarthritis = Hydrocortisone has a more dramatic effect • ESR (weekly) = Hydrocortisone causes a dramatic drop, which then increases upon withdrawal of treatment Salicylates have a lesser effect on ESR - Conduction time = More rapid return to normal in hormone groups (UNABLE TO USE DATA IN ANALYSIS) Notes

- Full-text paper - Supported by grant from National Heart Institute of US Public Health Service

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Unclear risk bias)

Not reported

Allocation concealment (selection bias)

Quote: “The therapeutic group for each patient was determined by a sealed envelope technique. The envelopes were so arranged that all forms of therapy were used during the entire period of the study in order to obviate temporal effects”

Low risk

Blinding of participants and personnel High risk (performance bias) All outcomes

Quote: “It was impossible for the observers to be ignorant of therapeutic groups because of the striking effects of hormone therapy”

Blinding of outcome assessment (detection High risk bias) All outcomes

Quote: “It was impossible for the observers to be ignorant of therapeutic groups because of the striking effects of hormone therapy”

Incomplete outcome data (attrition bias) All outcomes

High risk

16% of participants withdrew from the studies, died or were lost to follow-up

Selective reporting (reporting bias)

Unclear risk

Outcomes not clearly stated in Methods section, so difficult to assess

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Haffejee 1990 Methods

DESIGN - Prospective - Parallel ALLOCATION - Random BLINDING - Double-blind - Placebo-controlled - Identical placebo WITHDRAWALS - 5 described (prednisone 2, placebo 3)

Participants

INCLUSION CRITERIA - First episode of active rheumatic fever diagnosed according to Jones criteria 1965 and carditis - Carditis group subdivided into mild (apical pansystolic murmur), moderate (diastolic murmur) and severe (murmur plus cardiomegaly, cardiac failure or pericarditis) - Time to treatment not indicated RANDOMLY ASSIGNED (N = 35) - Prednisone = 19 - Placebo = 16 GRADING OF SEVERITY OF CARDITIS AT START - Mild (apical pansystolic murmur), moderate (systolic and diastolic murmurs) or severe (systolic and diastolic murmurs + Cardiomegaly and/or cardiac failure and/or pericarditis) WITHDRAWALS - Prednisone = 2 - Placebo = 2 - Death = 1 (in placebo group in acute stage) AGE (average in years) - Prednisone 9.7 (1.9) - Placebo 9.4 (1.64) SEX (M:F) - Prednisone 13:6 - Placebo 6:10

Interventions

TEST GROUP - Prednisone 2 mg/kg in 3 divided doses until clinical response (e.g. sleeping pulse < 80/ min, ESR < 30 mm/h, negative CRP) PLACEBO - Identical tablet CO-TREATMENT - Bed rest - Oral penicillin 250 mg 6-hourly - Digoxin - Diuretics - Potassium supplements - Salicylates for severe joint pain × 2 or 3 d

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Haffejee 1990

(Continued)

Outcomes

ANALYSIS - Intention-to-treat not specified PARTICIPANTS WITH MURMURS, SURGERY OR DEATH AT LONG-TERM FOLLOW-UP OF 15 MONTHS TO 6 YEARS (mean = 3 years and 11 months) - Prednisone = 14/17 (surgery = 4, died = 1) - Placebo = 6/13 (surgery = 1, died = 0) OUTCOME OF PARTICIPANTS WITH SEVERE CARDITIS - Prednisone: 5/8 died, or required surgery - Placebo: 1/4 required surgery OTHER SHORT-TERM OUTCOMES - No detailed analysis provided • Sleeping pulse • Fall in ESR • Negative CRP (recorded as similar in both groups)

Notes

- Full-text paper - Funding by the South African Research Council

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Unclear risk bias)

States only that codes were assigned in a randomised fashion, with no description

Allocation concealment (selection bias)

Low risk

Quote: “The tablets were given according to a numerical code which was known only to the chief hospital pharmacist, each patient being assigned a coded number in a randomised fashion the same number appearing on the tablet-container for a particular patient. The code was sealed and kept in a safe for the entire duration of the trial”

Blinding of participants and personnel Low risk (performance bias) All outcomes

Quote: “Neither the clinicians nor the patients were aware of what tablets were being administered, i.e. the trial was doubleblind”

Blinding of outcome assessment (detection Low risk bias) All outcomes

Quote: “Even at follow-up visits the investigator was unaware of the identity of the medication given to any particular patient. The code was not broken until 7 years after the initiation of the trial, after all the relevant patient data, including long term follow-up, had been collected”

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Haffejee 1990

(Continued)

Incomplete outcome data (attrition bias) All outcomes

Low risk

35 participants in total, 19 in prednisone, 16 in placebo; 2 in each group lost to follow-up

Selective reporting (reporting bias)

Unclear risk

Outcomes not clearly stated in Methods section, so difficult to assess

Massell 1961 Methods

DESIGN - Prospective - Consecutive participants in the first 3 study groups from 1941 to 1953 - Parallel arrangement for the last 2 study groups (groups 4 and 5) from 1953 onwards ALLOCATION (5 GROUPS) - Partial randomisation from 1954 = Groups 4 (N.C.S. Hormone) and 5 (N.C.S. Aspirin) - Other 3 groups consisted of “no therapy”, Small-Dose Hormone and Post-Co-op Hormone = Enrolled from 1941 to 1953, not randomly assigned (these 3 groups were not included in the analysis) BLINDING - Nil WITHDRAWALS (lost to follow-up after 1 year) - N.C.S. Hormone group = 3 - N.C.S. Aspirin group = 6

Participants

INCLUSION CRITERIA - First attack of rheumatic fever - Cardiac findings include cardiomegaly, pericarditis, congestive cardiac failure, significant apical systolic murmurs, aortic diastolic murmurs - Diagnosis of rheumatic fever according to Jones criteria not specified - Time to treatment not indicated RANDOMLY ASSIGNED (N = 99) - N.C.S. Hormone = 56 (separate data for each drug not provided) - N.C.S. Aspirin = 43 NO GRADING SYSTEM OF SEVERITY FOR RANDOMLY ASSIGNED PARTICIPANTS WITHDRAWALS (lost at 1-year follow-up) - N.C.S. Hormone group = 3 - N.C.S. Aspirin group = 6 AGE (average in years) - Not indicated SEX (M:F) - Not indicated

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Massell 1961

(Continued)

Interventions

TEST GROUP (corticosteroids in large doses) - ACTH 4200 U - Cortisone 15.5 g - Prednisone 3.1 g - Dexamethasone 310 mg × 12 wk CONTROL GROUP - Aspirin 40 mg/lb/d × 12 wk CO-TREATMENT - Not indicated

Outcomes

ANALYSIS - Intention-to-treat - Not specified PARTICIPANTS WITH “SIGNS OF RHEUMATIC HEART DISEASE” AT 1 YEAR - N.C.S. Hormone group = 31/53 - N.C.S. Aspirin group = 28/37 (further analysis performed at 2 years and 3 years) OTHER OUTCOMES - Not included in the study

Notes

- Full-text paper - Supported by grants from National Heart Institute, Massachusettes Heart Association, Barnstable County Chapter of the Massachusetts Heart Association, Schering Corporation, Merck Sharp and Dohme Research Laboratories

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection High risk bias)

Some participants in the groups “no therapy”, “post-co-op hormone” and “smalldose hormone” were consecutively allocated, but these participants were not included in the analysis Aspirin and hormone groups (included in analysis) were randomly assigned in some fashion Quote: “been selected at random for treatment with aspirin or hormones”, but no description was provided of what random selection was. However, because more participants were given hormones than aspirin, investigators included some participants who were given aspirin as part of another trial

Allocation concealment (selection bias)

Some participants given aspirin in another trial were included in the analysis

High risk

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Massell 1961

(Continued)

Blinding of participants and personnel High risk (performance bias) All outcomes

Not blinded

Blinding of outcome assessment (detection High risk bias) All outcomes

Not blinded

Incomplete outcome data (attrition bias) All outcomes

Low risk

Arms appear relatively similar

Selective reporting (reporting bias)

Unclear risk

List of outcomes assessed in the study not clearly outlined

RFWP 1955 Methods

DESIGN - Prospective - Parallel ALLOCATION - 2 treatment centres = UK and USA - Randomisation BLINDING - Nil WITHDRAWALS - 20 described

Participants

INCLUSION CRITERIA - New attack (no rheumatic activity 3 months before) of rheumatic fever diagnosed according to criteria of T. Duckett Jones (1944) 3 CARDIAC GROUPS (subdivided into exclusive groups according to presence or absence of apical systolic and basal diastolic murmurs) - Group A = No carditis, previously normal heart - Group B = Carditis, previously normal heart - Group C = Preexisting heart disease RANDOMLY ASSIGNED (N = 497) - 3 “duration from-onset” groups: 14 days, 15 to 42 days, 43 days and more BOTH UK AND US GROUPS ACTH = 162 < 14 d = 86, 15 to 42 d = 47, > 43 d = 29 Cortisone = 167 < 14 d = 85, 15 to 42 d = 45, > 43 d = 37 Aspirin = 168 < 14 d = 84, 15 to 42 d = 46, > 43 = 38 GRADE 3 SYSTOLIC MURMURS AT START (grading of murmurs from 0 to 3) - Group A: no carditis at start - Group B: ACTH = 20, cortisone = 16, Aspirin = 10 - Group C: ACTH = 16, cortisone = 16, Aspirin = 11

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RFWP 1955

(Continued)

EARLY WITHDRAWALS - Original N = 505 - 5 excluded at start because of incorrect diagnosis - 3 excluded from statistical analysis because treatment not completed TREATMENT STOPPED OR TREATMENT CHANGED DURING STUDY TREATMENT STOPPED - ACTH 4 (1 excluded from analysis by RFWP), Aspirin 1 TREATMENT CHANGED - Aspirin 5 (1 excluded from analysis by RFWP, remaining 4 were analysed in the groups to which they were initially randomly assigned) - Changed to ACTH 3, cortisone 2 RETREATMENT - Cortisone 2, Aspirin 2 TREATMENT INCOMPLETE - Cortisone 1 (excluded for analysis by RFWP) AGE (mean age in years) BOTH UK AND US GROUPS - ACTH = 10 - Cortisone = 10 - Aspirin = 9.9 SEX (M:F) BOTH UK AND US GROUPS - ACTH = 91:71 - Cortisone = 79:88 - Aspirin = 89:79 Interventions

TEST GROUP (corticosteroids) United Kingdom Group - ACTH = 80 USP units × 4 d, 60 USP units × 3 d, 40 USP units × 2 wk, 30 USP units × 2 wk, 20 USP units × 1 wk imi US group - ACTH 120 USP units × 4 d - 100 USP units × 3 d, 80 USP units × 1 wk, 60 USP units × 1 wk, 40 USP units × 2 wk, 20 USP units × 1 wk - Cortisone 300 mg × 1 d, 200 mg × 4 d, 100 mg × 3 wk, 75 mg × 2 wk, 50 mg × 1 wk imi CONTROL GROUP - Aspirin = 60 mg (1 grain)/lb/d × 2 d, 40 mg/lb/d × 5 d, 30 mg/lb/d × 5 wk po CO-TREATMENT - Low-sodium diet × 4 wk < 2 g/d - Potassium chloride 2 g/d if < 60 lb, 3 g/d if > 60 lb - Procaine penicillin G imi, 300,000 U if < 60 lb and 600,000 U if > 60 lb on admission day, day 4, day 7 and day 10 - Sulfadiazine on day 14, 0.5 g if < 60 lb, 1 g if > 60 lb - Bed rest × 9 wk

Outcomes

ANALYSIS - Intention-to-treat - Not specified

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RFWP 1955

(Continued)

MURMURS PRESENT AT 1 YEAR (includes groups A, B, C) APICAL SYSTOLIC MURMURS - ACTH = 84/162 - Cortisone = 73/167 - Acetylsalicylic acid = 71/168 BASAL DIASTOLIC MURMURS - ACTH = 17/162 - Cortisone = 20/167 - Acetylsalicylic acid = 16/168 GRADE 3 SYSTOLIC MURMURS AT 1 YEAR GROUP B: ACTH = 7/20, Cortisone = 9/16, Aspirin = 1/10 Group C: ACTH = 11/16, Cortisone = 8/16, Aspirin = 4/11 (the 2 groups analysed together) GROUP A: murmurs at the end of 1 year, no grading given - ACTH = 5/40 - Cortisone= 4/39 - Aspirin = 5/38 DEATHS AT 1 YEAR - ACTH = 1 - Cortisone = 2 - Aspirin = 3 PERICARDITIS AND/OR CONGESTIVE FAILURE AT 13 WEEKS (END OF THERAPY) - ACTH = 3/23 - Cortisone = 0/15 - Aspirin = 0/10 OTHER OUTCOMES (at 3 wk, 6 wk, 9 wk) - Temperature = Similar in all 3 groups at end of 9 wk - Sleeping pulse = Achievement of bradycardia slower in aspirin group - ESR = Decrease more rapid in hormone groups and increased in both groups after treatment was stopped because of rebound. Reached the same low level by 13 weeks in all 3 groups - Resolution of joint involvement, same effect in all 3 groups - Persistence of chorea was similar in all 3 groups - New subcutaneous nodules appeared in all 3 treatment groups, but persisted longer in the aspirin group than in hormone groups - Erythema marginatum = Appearance or disappearance of rash not related to therapy - Temporary increase in heart size with hormone treatment if cardio/thoracic ratio 0.6 or greater - Decrease in atrioventricular conduction time more rapid in hormone group initially Notes

- Full-text paper - Supported by grants from National Heart Institute of US Public Health Service, Medical Research Council of Great Britain, Canadian Arthritis and Rheumatism Society and American Heart Association

Risk of bias

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Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Unclear risk bias)

Quote: “Using random sampling numbers and keeping the numbers of patients on the three treatments approximately equal in each centre” Comment: random sampling numbers not stated, not stated whether stratification occurred

Allocation concealment (selection bias)

Quote: “The coordinating centre in each country issued serially numbered and sealed envelopes to the treatment centres. Thus, on admission of a patient of given age and specified duration-from-onset group, the investigator at the treatment centre had merely to open the next available envelope for that particular group to find a statement of the treatment to be applied”

Low risk

Blinding of participants and personnel Unclear risk (performance bias) All outcomes

Quote: “The allocation was both ”blind“ and random”; not described better than that

Blinding of outcome assessment (detection Unclear risk bias) All outcomes

Not reported

Incomplete outcome data (attrition bias) All outcomes

Low risk

No differences between arms apparent; all outcomes apparently reported; participants switching treatments apparently analysed in groups to which they were assigned

Selective reporting (reporting bias)

Unclear risk

All outcomes not clearly reported in Methods section

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

32

Stolzer 1955 Methods

DESIGN - Prospective - Parallel ALLOCATION - Randomisation BLINDING - 1 blinded observer for 87% of cases WITHDRAWALS - 17 described - 7 participants had underlying cardiac disease at start of therapy (ASA group = 1 participant, cortisone = 3, corticotrophin = 3). Analysed separately

Participants

INCLUSION CRITERIA - Rheumatic activity (128/135 = first attack of rheumatic fever) - Diagnosis of rheumatic activity according to Jones criteria not indicated - Final evaluations made at 14 months (by 1 of 3 observers) for cardiac murmurs = apical systolic, apical mid-diastolic murmurs and aortic diastolic murmurs - Average days of illness at time of treatment • ASA = 8 days • Cortisone = 8.3 days • Corticotrophin = 8.3 days RANDOMLY ASSIGNED (N = 152) 135 were followed × 14 mo - Cortisone = 41 - Corticotropin = 41 - Acetylsalicylic acid (ASA) = 53 (7 of these participants were analysed separately as patients with preexisting heart disease developing new murmurs) NO GRADING OF MURMURS PERFORMED. WITHDRAWALS - ASA = 10 - Cortisone = 4 - Corticotropin = 3 AGE - Not indicated SEX - All male (airmen)

Interventions

TEST GROUP (ASA) - 60 mg/lb orally days 1 to 2, 40 mg/lb days 3 to 7, 30 mg/lb days 8 to 42 CONTROL GROUP (corticosteroids) - Cortisone (imi) 300 mg day 1, 200 mg days 2 to 5, 100 mg days 6 to 21, 75 mg days 22 to 35, 50 mg days 36 to 42 - Corticotrophin (imi) 120 mg days 1 to 4, 100 mg days 5 to 7, 80 mg days 8 to 14, 60 mg days 15 to 21, 40 mg days 22 to 35, 20 mg days 36 to 42 CO-TREATMENT - Potassium chloride 3 g/d - Diet < 2 g/d of sodium chloride × 4 wk - Penicillin

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

33

Stolzer 1955

(Continued)

- Then sulfadiazine 1 to 1.5 g/d - Bed rest × 9 wk Outcomes

ANALYSIS - Intention-to-treat not specified SIGNIFICANT APICAL SYSTOLIC MURMURS AT 14 MONTHS - Cortisone = 7/38 - Corticotrophin = 13/38 - ASA = 18/52 AORTIC DIASTOLIC MURMURS AT 14 MONTHS - Cortisone = 0/38 - Corticotrophin = 1/38 - ASA = 2/52 MITRAL MID-DIASTOLIC MURMURS AT 14 MONTHS - Cortisone = 0/38 - Corticotrophin = 0/38 - ASA = 3/52 OUTCOME OF PARTICIPANTS WITH PREEXISTING HEART DISEASE DEVELOPING NEW MURMURS WITH TREATMENT - Cortisone = 3/3 - Corticotrophin = 2/3 - ASA = 1/1 (all murmurs were added together for review analysis) OTHER OUTCOMES - PR interval = Shortened more rapidly in hormone group - Heart size on CXR = Increase in heart size in hormone groups at 4 weeks. At 9 weeks, heart size the same as at onset of treatment in all 3 groups - Heart failure = 1 participant in each treatment group. Heart failure improved within 7 days in all 3 participants - Pericarditis = 1 participant in the cortisone group and 1 in the ASA group. Pericardial friction rub disappeared within 6 days in both groups - Joints = ASA afforded the most prompt relief of joint manifestations - ESR = Corticotrophin had the most marked effect in lowering ESR

Notes

- Full-text paper - Sponsorship from Commission on Acute Respiratory Diseases and Commission on Streptococcal Diseases, Armed Forces Epidemiological Board and Offices of The Surgeon General, Departments of the Army and the Air Force, Washington DC

Risk of bias Bias

Authors’ judgement

Random sequence generation (selection Unclear risk bias)

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Support for judgement Quote: “Each patient was assigned a number in consecutive fashion, and the selection of the form of therapy was predetermined in a random fashion” Comment: The random fashion was not 34

Stolzer 1955

(Continued)

described Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel Unclear risk (performance bias) All outcomes

Not reported

Blinding of outcome assessment (detection Low risk bias) All outcomes

Quote: “An independent observer, who knew nothing of the patient’s history, previous or present cardiac findings, or therapy, examined 87% of the patients between the 10th and 16th month after the start of therapy. Complete agreement on the presence or absence of a murmur and its significance was obtained in 76% of the patients”

Incomplete outcome data (attrition bias) All outcomes

Low risk

All outcomes apparently reported with all participants

Selective reporting (reporting bias)

Low risk

All outcomes apparently reported

Voss 2001 Methods

DESIGN - Prospective - Parallel group ALLOCATION - Random BLINDING - Double-blind - Placebo-controlled - Identical placebo WITHDRAWALS - 2 described in IVIG group

Participants

INCLUSION CRITERIA - First episode of rheumatic fever diagnosed according to Jones criteria 1965 and 1992 - Time to treatment not indicated RANDOMLY ASSIGNED (N = 61) - Intravenous immunoglobulin (IVIG) = 29 - Placebo = 32 CARDITIS (N = 39) IVIG = 17, placebo = 22 SEVERITY OF CARDITIS BASED ON ECHOCARDIOGRAPHIC FINDINGS AT START - SEVERE: IVIG = 0, placebo = 2 - MODERATE: IVIG = 6, placebo = 9

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Voss 2001

(Continued)

- MILD: IVIG = 8, placebo = 9 - SUBCLINICAL: IVIG = 9, placebo = 9 WITHDRAWALS - IVIG = 2 AGE (average in years) - IVIG = 11.2 (2) - Placebo = 11 (3) SEX (M:F) - IVIG = 14:13 - Control = 19:13 Interventions

TEST GROUP - IVIG 1 g/kg days 0 and 1, then 0.4 mg/kg days 14 and 28 CONTROL GROUP - Placebo (4% dextrose, 0.18% normal saline) CO-TREATMENT - Bed/chair rest × 2 wk - Oral penicillin × 2 wk - imi benzathine penicillin at discharge - Salicylates for relief of arthritis

Outcomes

ANALYSIS - Intention-to-treat not specified PRESENCE OF CARDITIS AT 1 YEAR (CARDITIS = defined by the presence of an aortic or mitral murmur clinically and aortic or mitral regurgitation by echocardiographic evaluation; echocardiography adds only a few more participants) PARTICIPANTS WITH CARDITIS AT 1 YEAR - IVIG = 14/27 (2 withdrawals) - Placebo = 19/32 CARDIAC OUTCOMES ACCORDING TO SEVERITY AT 1 YEAR - SEVERE: IVIG = 1, placebo = 1/2 - MOD: IVIG = 2/6, placebo = 6/9 - MILD: IVIG = 4/8, placebo = 4/9 - SUBCLINICAL: IVIG = 7/9, placebo = 8/9 (moderate & severe groups analysed together) OTHER OUTCOMES - ESR and CRP similar in the 2 groups at 6-week follow-up. ESR was significantly higher in IVIG group at 2 weeks, but this did not persist

Notes

- Full-text paper - Funding by National Heart Foundation of New Zealand

Risk of bias Bias

Authors’ judgement

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Support for judgement

36

Voss 2001

(Continued)

Random sequence generation (selection Low risk bias)

Quote: “Randomisation was by smallgroup, random-number allocation”

Allocation concealment (selection bias)

Not reported

Unclear risk

Blinding of participants and personnel Low risk (performance bias) All outcomes

Quote: “Double-blind, placebo-controlled trial”

Blinding of outcome assessment (detection Low risk bias) All outcomes

Quote: “...cardiologists were unaware of the nature of the infusion being administered”

Incomplete outcome data (attrition bias) All outcomes

Unclear risk

Not all numbers reported

Selective reporting (reporting bias)

High risk

2 minor outcomes (tricuspid and pulmonary regurgitation) listed in the Methods do not appear to have been reported in the Results

AI = aortic incompetence; ASA = aspirin or acetylsalicylic acid; DB = double-blinded; MI = myocardial infarction; SB = sIngle-blinded.

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Akcoral 1996

Not a randomised trial. 18 participants with a diagnosis of acute rheumatic carditis and no steroids or salicylates given in the preceding 2 wk were given intravenous high-dose methylprednisolone

Bywaters 1956

Review study

Bywaters 1961

Review of participants who participated in the Cooperative Clinical Trial of ACTH, Cortisone and Aspirin in 1955. See RFWP 1955 in included studies

Camara 2002

Randomised clinical trial, but does not meet inclusion criterion of follow-up of at least 3 months. Participants followed up for only 4 weeks

Couto 1987

Not a randomised trial. Duration of illness was compared in 13 participants receiving oral corticosteroids and 13 receiving pulse therapy

Czoniczer 1964

Not a randomised trial. Retrospective analysis

Done 1955

Not a randomised trial. Mode of treatment assignment not clear

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

37

(Continued)

Ferencz 1959

Not a randomised trial. Prednisone was administered to all selected participants

Friedman 1962

Not a randomised trial. Follow-up study of participants receiving cortisone, ACTH and no specific therapy sequentially 6 to 9 years earlier

Hashkes 2003

Randomised trial assessing use of naproxen as an alternative to aspirin in the treatment of arthritis of rheumatic fever. Inclusion criteria not met

Herdy 1993

Not a randomised trial. 36 participants with rheumatic carditis given high doses of intravenous methylprednisolone

Herdy 1999

Not a randomised trial. 70 children with active rheumatic fever treated with intravenous boluses of methylprednisolone 3 times a week

Herdy 2012

Not a randomised trial. Retrospective analysis of outcomes of 242 participants with severe rheumatic carditis after discharge and treated with intravenous methylprednisolone or oral prednisone

Human 1984

Not a randomised trial. 3 study groups of moderate cardiac disease, severe heart disease and life-threatening heart disease alternatively assigned to treatment with prednisone or salicylates. Outcomes assessed were clinical response, ESR response and hospital stay in days

Marshall 1989

Letter

McCue 1957

Not a randomised trial. Varying doses of cortisone administered orally to participants with active rheumatic fever

Morino 1973

Not a randomised trial. Reported outcomes were acute phase reactants. No cardiac outcomes outlined

Naik 2002

Review article

Narin 2003

Not a randomised trial. Cardiac outcomes assessed after 3 months. Outcome data not given as numbers of patients responding to treatment, but rather as a mean

Okuni 1975

Not a randomised trial. 111 participants with rheumatic carditis treated with steroids

Paz 2006

Participants did not have carditis

Rowe 1953

Randomised controlled trial, but does not meet inclusion criterion of follow-up of at least 3 months

Singh 1998

Letter

Uziel 2000

Not a randomised trial. Retrospective review of participants with diagnosis of rheumatic fever treated with naproxen

Wilson 1953

Not a randomised trial. Corticotropin administered to 28 participants with 32 attacks of active carditis. Control observations made on 7 participants who did not receive corticotropin

Wilson 1959

Not a randomised trial. Participants with active rheumatic carditis treated with short-term steroids for 7 days

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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DATA AND ANALYSES

Comparison 1. Corticosteroids versus aspirin

Outcome or subgroup title 1 Cardiac disease after 1 year 2 Outcome of severe cardiac disease after 1 year

No. of studies

No. of participants

6 3

907 119

Statistical method Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

Effect size 0.87 [0.66, 1.15] 0.94 [0.32, 2.70]

Comparison 2. Individual corticosteroids versus aspirin

Outcome or subgroup title 1 Cardiac disease after 1 year 1.1 Hydrocortisone versus aspirin 1.2 Prednisone versus aspirin

No. of studies

No. of participants

3 1

276 64

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

0.86 [0.42, 1.76] 0.43 [0.19, 0.97]

2

212

Risk Ratio (M-H, Random, 95% CI)

1.13 [0.52, 2.45]

Statistical method

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Effect size

39

Analysis 1.1. Comparison 1 Corticosteroids versus aspirin, Outcome 1 Cardiac disease after 1 year. Review:

Anti-inflammatory treatment for carditis in acute rheumatic fever

Comparison: 1 Corticosteroids versus aspirin Outcome: 1 Cardiac disease after 1 year

Study or subgroup

Corticosteroids

Aspirin

Risk Ratio MH,Random,95% CI

Weight

Risk Ratio MH,Random,95% CI

n/N

n/N

19/34

26/39

18.5 %

0.84 [ 0.58, 1.22 ]

6/32

14/32

8.1 %

0.43 [ 0.19, 0.97 ]

Massell 1961

31/53

28/37

21.3 %

0.77 [ 0.58, 1.03 ]

CRFSG 1960

16/28

9/27

11.6 %

1.71 [ 0.92, 3.19 ]

RFWP 1955

197/329

90/168

25.2 %

1.12 [ 0.95, 1.32 ]

Stolzer 1955

21/76

23/52

15.3 %

0.62 [ 0.39, 1.00 ]

552

355

100.0 %

0.87 [ 0.66, 1.15 ]

CRFSG 1965 Dorfman 1961

Total (95% CI)

Total events: 290 (Corticosteroids), 190 (Aspirin) Heterogeneity: Tau2 = 0.07; Chi2 = 16.04, df = 5 (P = 0.01); I2 =69% Test for overall effect: Z = 0.97 (P = 0.33) Test for subgroup differences: Not applicable

0.1 0.2

0.5

Favours Steroid

1

2

5

10

Favours Aspirin

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Analysis 1.2. Comparison 1 Corticosteroids versus aspirin, Outcome 2 Outcome of severe cardiac disease after 1 year. Review:

Anti-inflammatory treatment for carditis in acute rheumatic fever

Comparison: 1 Corticosteroids versus aspirin Outcome: 2 Outcome of severe cardiac disease after 1 year

Study or subgroup

CRFSG 1960

Corticosteroid

Aspirin

Weight

Risk Ratio MH,Random,95% CI

n/N

n/N

12/12

9/9

42.2 %

1.00 [ 0.84, 1.20 ]

1/6

3/3

23.5 %

0.24 [ 0.06, 1.06 ]

35/68

5/21

34.3 %

2.16 [ 0.97, 4.81 ]

86

33

100.0 %

0.94 [ 0.32, 2.70 ]

Dorfman 1961 RFWP 1955

Risk Ratio MH,Random,95% CI

Total (95% CI)

Total events: 48 (Corticosteroid), 17 (Aspirin) Heterogeneity: Tau2 = 0.69; Chi2 = 12.17, df = 2 (P = 0.002); I2 =84% Test for overall effect: Z = 0.12 (P = 0.90) Test for subgroup differences: Not applicable

0.1 0.2

0.5

Favours Steroid

1

2

5

10

Favours Aspirin

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Analysis 2.1. Comparison 2 Individual corticosteroids versus aspirin, Outcome 1 Cardiac disease after 1 year. Review:

Anti-inflammatory treatment for carditis in acute rheumatic fever

Comparison: 2 Individual corticosteroids versus aspirin Outcome: 1 Cardiac disease after 1 year

Study or subgroup

Hormone

Aspirin

Risk Ratio MH,Random,95% CI

Weight

Risk Ratio MH,Random,95% CI

n/N

n/N

6/32

14/32

28.5 %

0.43 [ 0.19, 0.97 ]

32

32

28.5 %

0.43 [ 0.19, 0.97 ]

1 Hydrocortisone versus aspirin Dorfman 1961

Subtotal (95% CI) Total events: 6 (Hormone), 14 (Aspirin) Heterogeneity: not applicable

Test for overall effect: Z = 2.02 (P = 0.043) 2 Prednisone versus aspirin CRFSG 1960

16/28

9/27

33.9 %

1.71 [ 0.92, 3.19 ]

CRFSG 1965

20/78

26/79

37.5 %

0.78 [ 0.48, 1.27 ]

106

106

71.5 %

1.13 [ 0.52, 2.45 ]

100.0 %

0.86 [ 0.42, 1.76 ]

Subtotal (95% CI) Total events: 36 (Hormone), 35 (Aspirin)

Heterogeneity: Tau2 = 0.23; Chi2 = 3.82, df = 1 (P = 0.05); I2 =74% Test for overall effect: Z = 0.31 (P = 0.76)

Total (95% CI)

138

138

Total events: 42 (Hormone), 49 (Aspirin) Heterogeneity: Tau2 = 0.29; Chi2 = 7.66, df = 2 (P = 0.02); I2 =74% Test for overall effect: Z = 0.42 (P = 0.68) Test for subgroup differences: Chi2 = 2.83, df = 1 (P = 0.09), I2 =65%

0.1 0.2

0.5

Favours hormone

1

2

5

10

Favours aspirin

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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APPENDICES Appendix 1. Glossary Acetylsalicylic acid (ASA) Type of anti-inflammatory analgesic; also called aspirin. ACTH Corticotrophin. Anticoagulant therapy Use of anticoagulant drugs to reduce or prevent intravascular or intracardiac clotting. Aspirin Type of anti-inflammatory analgesic; also called acetylsalicylic acid (ASA). Auscultation Act of listening for sounds within the body. Carditis Inflammation of the heart, including pericarditis, myocarditis and endocarditis, according to whether the enveloping outer membrane, the muscle or the inner lining is affected. C-reactive protein (CRP) Blood test used as an indicator of acute inflammation. C-reactive protein is a protein of the pentraxin family, produced by the liver during periods of inflammation and detectable in serum in various disease conditions, particularly during acute phases of immune response. Normally C-reactive protein should be negative in the bloodstream. Endocardium Innermost lining of the heart cavities. Erythrocyte sedimentation rate (ESR) Test that measures the rate at which red blood cells settle through a column of liquid. Non-specific index of inflammation. Heart valves One-way inlets or outlets between heart chambers that allow blood to be pumped in the appropriate direction. The heart has four main valves: tricuspid, mitral, aortic and pulmonic valves. Intravenous immunoglobulin (IVIG) Sterile solution of concentrated antibodies extracted from healthy people. IVIG is used to prevent bacterial infection in people with low or inappropriate antibody production. Injected into a vein or muscle. Lesion Any pathological or traumatic discontinuity of tissue or loss of function of a part. Mitral valve Heart valve that divides the left atrium and the left ventricle. During left atrial contraction, the mitral valve opens to allow blood to flow into the left ventricle. Upon closure, the mitral valve prohibits regurgitation of blood back into the left atrium. The mitral valve is the only heart valve that has only two valve cusps (all others have three). Murmur Noise found on physical examination of the heart that can, in some cases, indicate the presence of cardiac disease. Murmurs result from vibrations set up in the bloodstream and surrounding heart and great vessels as the result of turbulent flow. Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Myocardial (Myocardium) Term used to describe the middle layer of the heart wall (heart muscle). Pentoxifylline Drug that is a methylxanthine derivative with diverse pharmacological properties that cause inhibition of inflammation. P-R interval (also called PQ interval) In the electrocardiogram, time elapsing between beginning of the P wave and beginning of the next QRS complex; corresponds to the a-c interval of the venous pulse and is normally 0.12 to 0.20 seconds. Pericardium Double membranous sac that envelopes and protects the heart. Layer in contact with the heart is referred to as the visceral layer; the outer layer in contact with surrounding organs is the parietal pericardium. Between the two layers is the pericardial space. Regurgitant heart valve Valve fails to close properly and causes regurgitation of blood flow (flowing backward). Salicylates Type of anti-inflammatory analgesic; includes aspirin (acetylsalicylic acid). Sequelae Condition following as a consequence of a disease. Stenotic heart valve Heart valve fails to open properly. Warfarin (warfarin sodium). Oral anticoagulant used for prophylaxis of embolisation in rheumatic heart disease. Acetylsalicylic Acid (ASA) Type of anti-inflammatory analgesic; also called aspirin. ACTH Corticotrophin. Anticoagulant therapy Use of anticoagulant drugs to reduce or prevent intravascular or intracardiac clotting. Aspirin Type of anti-inflammatory analgesic; also called acetylsalicylic acid (ASA). Auscultation Act of listening for sounds within the body. Carditis Inflammation of the heart, including pericarditis, myocarditis and endocarditis, according to whether the enveloping outer membrane, the muscle or the inner lining is affected. C-reactive protein (CRP) Blood test used as an indicator of acute inflammation. C-reactive protein is a protein of the pentraxin family, produced by the liver during periods of inflammation and detectable in serum in various disease conditions, particularly during acute phases of immune response. Normally C-reactive protein should be negative in the bloodstream. Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Endocardium Innermost lining of the heart cavities. Erythrocyte sedimentation rate (ESR) Test that measures the rate at which red blood cells settle through a column of liquid. Non-specific index of inflammation. Heart valves One-way inlets or outlets between heart chambers that allow blood to be pumped in the appropriate direction. The heart has four main valves: tricuspid, mitral, aortic and pulmonic valves. Intravenous immunoglobulin (IVIG) Sterile solution of concentrated antibodies extracted from healthy people. IVIG is used to prevent bacterial infection in people with low or inappropriate antibody production. Injected into a vein or muscle. Lesion Any pathological or traumatic discontinuity of tissue or loss of function of a part. Mitral valve Heart valve that divides the left atrium and the left ventricle. During left atrial contraction, the mitral valve opens to allow blood to flow into the left ventricle. Upon closure, the mitral valve prohibits regurgitation of blood back into the left atrium. The mitral valve is the only heart valve that has only two valve cusps (all others have three). Murmur Noise found on physical examination of the heart that can, in some cases, indicate the presence of cardiac disease. Murmurs result from vibrations set up in the bloodstream and surrounding heart and great vessels as the result of turbulent flow. Myocardial (Myocardium) Term used to describe the middle layer of the heart wall (heart muscle). Pentoxifylline Drug that is a methylxanthine derivative with diverse pharmacological properties that causes inhibition of inflammation. P-R interval (also called PQ interval) In the electrocardiogram, time elapsing between beginning of the P wave and beginning of the next QRS complex; corresponds to the a-c interval of the venous pulse and is normally 0.12 to 0.20 seconds. Pericardium Double membranous sac that envelopes and protects the heart. Layer in contact with the heart is referred to as the visceral layer; the outer layer in contact with surrounding organs is the parietal pericardium. Between the two layers is the pericardial space. Regurgitant heart valve Valve fails to close properly and causes regurgitation of blood flow (flowing backward). Salicylates Type of anti-inflammatory analgesic; includes aspirin (acetylsalicylic acid). Sequelae Conditions following as a consequence of a disease. Stenotic heart valve Heart valve fails to open properly. Warfarin (warfarin sodium). Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Oral anticoagulant used for prophylaxis of embolisation in rheumatic heart disease.

Appendix 2. 2013 search strategies

CENTRAL #1MeSH descriptor: [Rheumatic Fever] explode all trees #2(rheumat* near/6 fever*) #3(rheumat* near/6 acute) #4rhd #5(rheumat* and streptococc*) #6(rheumat* near/6 polyarthrit*) #7(arthrit* and streptococc*) #8MeSH descriptor: [Chorea] this term only #9chorea #10carditis #11(streptococc* and heart) #12(streptococc* and card*) #13(rheumat* and fever) #14#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 #15MeSH descriptor: [Anti-Inflammatory Agents] explode all trees #16MeSH descriptor: [Antirheumatic Agents] explode all trees #17antiinflam* #18anti-inflam* #19(inflammation near/6 mediator*) #20(antirheumatic* near/6 agent*) #21corticosteroid* #22steroid* #23nsaid* #24salicylat* #25aspirin* #26prednisone* #27cortisone #28hydrocortisone #29dexamethasone #30intravenous next immunoglobulin* #31ivig #32acetylsalicylic* #33corticotropin* #34acth #35corticotrophin #36pentoxifylline #37#15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 #38#27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 #39#37 or #38 #40#14 and #39

MEDLINE 1. exp Rheumatic Fever/ 2. Rheumatic Heart Disease/ Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

46

3. (rheumat$ adj3 fever$).tw. 4. (rheumat$ adj3 card$).tw. 5. (rheumat$ adj3 heart$).tw. 6. (rheumat$ adj3 valv$).tw. 7. or/1-6 8. exp Anti-Inflammatory Agents/ 9. exp Antirheumatic Agents/ 10. Aspirin/ 11. corticosteroid$.tw. 12. prednisone.tw. 13. aspirin.tw. 14. acetylsalicyl$.tw. 15. (antiinflam$ or anti-inflam$).tw. 16. Adrenocorticotropic Hormone/ 17. acetylsalicylic.tw. 18. hydrocortisone.tw. 19. corticotrophin.tw. 20. corticotropin.tw. 21. acth.tw. 22. dexamethasone.tw. 23. Immunoglobulins, Intravenous/ 24. ivig.tw. 25. immunoglobulin$.tw. 26. Pentoxifylline/ 27. pentoxifylline.tw. 28. or/8-27 29. 7 and 28 30. randomized controlled trial.pt. 31. controlled clinical trial.pt. 32. randomized.ab. 33. placebo.ab. 34. drug therapy.fs. 35. randomly.ab. 36. trial.ab. 37. groups.ab. 38. 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 39. exp animals/ not humans.sh. 40. 38 not 39 41. 29 and 40 42. (2011* or 2012* or 2013*).ed. 43. 41 and 42

EMBASE 1. rheumatic fever/ 2. rheumatic heart disease/ 3. (rheumat$ adj3 fever$).tw. 4. (rheumat$ adj3 card$).tw. 5. (rheumat$ adj3 heart$).tw. 6. (rheumat$ adj3 valv$).tw. 7. or/1-6 8. exp antiinflammatory agent/ 9. corticosteroid therapy/ Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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10. exp corticosteroid/ 11. acetylsalicylic acid/ 12. corticosteroid$.tw. 13. prednisone.tw. 14. aspirin.tw. 15. acetylsalicyl$.tw. 16. (antiinflam$ or anti-inflam$).tw. 17. corticotropin/ 18. acetylsalicylic.tw. 19. hydrocortisone.tw. 20. corticotrophin.tw. 21. corticotropin.tw. 22. acth.tw. 23. dexamethasone.tw. 24. exp immunoglobulin/ 25. immunoglobulin$.tw. 26. pentoxifylline/ 27. Pentoxifylline.tw. 28. or/8-27 29. 28 and 7 30. random$.tw. 31. factorial$.tw. 32. crossover$.tw. 33. cross over$.tw. 34. cross-over$.tw. 35. placebo$.tw. 36. (doubl$ adj blind$).tw. 37. (singl$ adj blind$).tw. 38. assign$.tw. 39. allocat$.tw. 40. volunteer$.tw. 41. crossover procedure/ 42. double blind procedure/ 43. randomized controlled trial/ 44. single blind procedure/ 45. 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 46. (animal/ or nonhuman/) not human/ 47. 45 not 46 48. 29 and 47 49. limit 48 to embase 50. (2011* or 2012* or 2013*).dd. 51. (2011* or 2012* or 2013*).em. 52. 50 or 51 53. 49 and 52 LILACS (carditis or rheumat$) [Words] and (anti-inflam$ or antiinflam$ or antirheum$) [Words] and random$ [Words]

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Appendix 3. 2011 search strategies

CENTRAL (2011) #1 MeSH descriptor RHEUMATIC FEVER explode all trees #2 (rheumat* near/6 fever*) #3 (rheumat* near/6 acute) #4 rhd #5 (rheumat* and streptococc*) #6 (rheumat* near/6 polyarthrit*) #7 (arthrit* and streptococc*) #8 MeSH descriptor CHOREA this term only #9 chorea #10 carditis #11 (streptococc* and heart) #12 (streptococc* and card*) #13 ( (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12) #14 MeSH descriptor ANTI-INFLAMMATORY AGENTS explode all trees #15 MeSH descriptor ANTIRHEUMATIC AGENTS explode all trees #16 antiinflam* #17 anti-inflam* #18 (inflammation near/6 mediator*) #19 (antirheumatic* near/6 agent*) #20 corticosteroid* #21 steroid* #22 nsaid* #23 salicylat* #24 aspirin* #25 prednisone* #26 (#14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25) #27 (#13 and #26) #28 cortisone #29 hydrocortisone #30 dexamethasone #31 intravenous next immunoglobulin* #32 ivig #33 acetylsalicylic* #34 corticotropin* #35 acth #36 corticotrophin #37 (rheumat* and fever) #38 pentoxifylline #39 (#28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38) #40 (#39 and #13) #41 (#27 or #40) MEDLINE (Ovid) 2011 1. exp Rheumatic Fever/ 2. Rheumatic Heart Disease/ 3. (rheumat$ adj3 fever$).tw. 4. (rheumat$ adj3 card$).tw. 5. (rheumat$ adj3 heart$).tw. Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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6. (rheumat$ adj3 valv$).tw. 7. or/1-6 8. exp Anti-Inflammatory Agents/ 9. exp Antirheumatic Agents/ 10. Aspirin/ 11. corticosteroid$.tw. 12. prednisone.tw. 13. aspirin.tw. 14. acetylsalicyl$.tw. 15. (antiinflam$ or anti-inflam$).tw. 16. Adrenocorticotropic Hormone/ 17. acetylsalicylic.tw. 18. hydrocortisone.tw. 19. corticotrophin.tw. 20. corticotropin.tw. 21. acth.tw. 22. dexamethasone.tw. 23. Immunoglobulins, Intravenous/ 24. ivig.tw. 25. immunoglobulin$.tw. 26. Pentoxifylline/ 27. pentoxifylline.tw. 28. or/8-27 29. 7 and 28 30. randomized controlled trial.pt. 31. controlled clinical trial.pt. 32. randomized.ab. 33. placebo.ab. 34. drug therapy.fs. 35. randomly.ab. 36. trial.ab. 37. groups.ab. 38. 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 39. exp animals/ not humans.sh. 40. 38 not 39 41. 29 and 40

EMBASE (Ovid) 2011 1. rheumatic fever/ 2. rheumatic heart disease/ 3. (rheumat$ adj3 fever$).tw. 4. (rheumat$ adj3 card$).tw. 5. (rheumat$ adj3 heart$).tw. 6. (rheumat$ adj3 valv$).tw. 7. or/1-6 8. exp antiinflammatory agent/ 9. corticosteroid therapy/ 10. exp corticosteroid/ 11. acetylsalicylic acid/ 12. corticosteroid$.tw. 13. prednisone.tw. 14. aspirin.tw. Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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15. acetylsalicyl$.tw. 16. (antiinflam$ or anti-inflam$).tw. 17. corticotropin/ 18. acetylsalicylic.tw. 19. hydrocortisone.tw. 20. corticotrophin.tw. 21. corticotropin.tw. 22. acth.tw. 23. dexamethasone.tw. 24. exp immunoglobulin/ 25. immunoglobulin$.tw. 26. pentoxifylline/ 27. Pentoxifylline.tw. 28. or/8-27 29. 28 and 7 30. random$.tw. 31. factorial$.tw. 32. crossover$.tw. 33. cross over$.tw. 34. cross-over$.tw. 35. placebo$.tw. 36. (doubl$ adj blind$).tw. 37. (singl$ adj blind$).tw. 38. assign$.tw. 39. allocat$.tw. 40. volunteer$.tw. 41. crossover procedure/ 42. double blind procedure/ 43. randomized controlled trial/ 44. single blind procedure/ 45. 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 46. (animal/ or nonhuman/) not human/ 47. 45 not 46 48. 29 and 47

LILACS (carditis or rheumat$) [Words] and (anti-inflam* or antiinflam$ or antirheum$)

Appendix 4. 2002 search strategies

CENTRAL search strategy - 2002 version #1 RHEUMATIC-FEVER*:ME #2 (RHEUMAT* and FEVER*) #3 (RHEUMAT* near ACUTE) #5 RHD #6 (RHEUMAT* and STREPTOCOCC*) #7 (RHEUMAT* near POLYARTHRIT*) #8 (ARTHRIT* and STREPTOCOCC*) #9 CHOREA:ME Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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#10 CHOREA #11 CARDITIS #12 (STREPTOCOCC* and HEART) #13 (STREPTOCOCC* and CARD*) #14 (((((((((((#1 or #2) or #3) or #4) or #5) or #6) or #7) or #8) or #9) or #10) or #11) or #12) #15 ANTI-INFLAMMATORY-AGENTS*:ME #16 ANTIRHEUMATIC-AGENTS*:ME #17 ANTIINFLAM* #18 ANTI-INFLAM* #19 (INFLAMMATION near MEDIATOR*) #20 (ANTIRHEUMATIC* near AGENT*) #21 CORTICOSTEROID* #22 STEROID* #23 NSAID* #24 SALICYLAT* #25 ASPIRIN* #26 PREDNISONE* #27 (((((((((((#14 or #15) or #16) or #17) or #18) or #19) or #20) or #21) or #22) or #23) or #24) or #25) #28 (#14 and #27)

MEDLINE (Ovid) 2002 1 exp Rheumatic Fever/ 2 Rheumatic Heart Disease/ 3 (rheumat$ adj3 fever$).tw. 4 (rheumat$ adj3 card$).tw. 5 (rheumat$ adj3 heart$).tw. 6 (rheumat$ adj3 valv$).tw. 7 or/1-6 8 exp Anti-Inflammatory Agents/ 9 exp Antirheumatic Agents/ 10 Acetylsalicylic Acid/ 11 corticosteroid$.tw. 12 prednisone.tw. 13 aspirin.tw. 14 acetylsalicyl$.tw. 15 (antiinflam$ or anti-inflam$).tw. 16 Corticotropin/ 17 acetylsalicylic.tw. 18 hydrocortisone.tw. 19 corticotrophin.tw. 20 corticotropin.tw. 21 acth.tw. 22 dexamethasone.tw. 23 Immunoglobulins, Intravenous/ 24 ivig.tw. 25 immunoglobulin$.tw. 26 Pentoxifylline/ 27 pentoxifylline.tw. 28 or/8-27 29 7 and 28

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EMBASE (Ovid) 2002 1 Rheumatic Fever/ 2 Rheumatic Heart Disease/ 3 (rheumat$ adj3 fever$).tw. 4 (rheumat$ adj3 card$).tw. 5 (rheumat$ adj3 heart$).tw. 6 (rheumat$ adj3 valv$).tw. 7 or/1-6 8 exp Antiinflammatory Agent/ 9 corticosteroid therapy/ 10 exp corticosteroid/ 11 Acetylsalicylic Acid/ 12 corticosteroid$.tw. 13 prednisone.tw. 14 aspirin.tw. 15 acetylsalicyl$.tw. 16 (antiinflam$ or anti-inflam$).tw. 17 Corticotropin/ 18 acetylsalicylic.tw. 19 hydrocortisone.tw. 20 corticotrophin.tw. 21 corticotropin.tw. 22 acth.tw. 23 dexamethasone.tw. 24 exp Immunoglobulin/ 25 immunoglobulin$.tw. 26 Pentoxifylline/ 27 Pentoxifylline.tw. 28 or/8-27 29 28 and 7 30 controlled study/ 31 clinical trial/ 32 major clinical study/ 33 random$.tw. 34 randomized controlled trial/ 35 trial$.tw. 36 compar$.tw. 37 control$.tw. 38 follow-up.tw. 39 blind$.tw. 40 double blind procedure/ 41 placebo$.tw. 42 clinical article/ 43 placebo/ 44 doubl$.tw. 45 or/30-44 46 45 and 29

LILACS (carditis or rheumat$) [Words] and (anti-inflam* or antiinflam$ or antirheum$) Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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WHAT’S NEW Last assessed as up-to-date: 17 October 2013.

Date

Event

Description

14 April 2016

Review declared as stable

no new studies since 2009, no known ongoing studies

HISTORY Protocol first published: Issue 3, 2001 Review first published: Issue 2, 2003

Date

Event

Description

8 November 2013

New citation required but conclusions have not We identified no new randomised controlled studies. changed Conclusions remain unchanged

17 October 2013

New search has been performed

We updated the search to 17 October 2013.

3 June 2012

New search has been performed

Updated in Cochrane Database Syst Rev 2012;6: CD003176

21 November 2011

New search has been performed

We updated the search to September 2011: We checked 78 new references and identified no new studies. Conclusions remain unchanged

22 July 2009

New search has been performed

We updated the search to June 2009: We checked 507 new references and identified no new studies. Conclusions remain unchanged

8 September 2008

Amended

Converted to new review format.

19 June 2007

New search has been performed

Updated July 2007. For this update, we conducted the search for primary studies up to June 2007. We made minor changes to update the search strategy. We found 1 randomised double-blind study related to the study topic (Paz 2006), but we excluded this study because it assessed the persistence of choreic movements after treatment with prednisone in patients with the diagnosis of Sydenham’s chorea. Study conclusions have not changed.

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(Continued)

2 May 2005

New search has been performed

Updated May 2005. For this update, we reran the search for primary studies up to April 2005. We found 4 new studies and excluded all of them from this review. One study was a review (Naik 2002), one was not a randomised trial (Narin 2003) and as the remaining 2 trials were randomised clinical trials, their outcomes were not relevant. One study had arthritis as the outcome (Hashkes 2003), and the other assessed participants 4 weeks after treatment (Camara 2002). Study conclusions have not been amended. Minor changes have been made to the Background. No changes have been made to the Methods. Search strategies remain unchanged

26 November 2002

New citation required and conclusions have changed

Substantive amendments were made.

CONTRIBUTIONS OF AUTHORS AMC. Conceived of, designed and co-ordinated the review. Responsible for collecting and developing the research strategy, screening search results, organising retrieval of and screening papers, appraising the quality of papers, abstracting data, managing data for the review, entering data into RevMan, analysing and interpreting data, providing a methodological and clinical perspective, writing the review and performing previous work that was the foundation of the current study. AJA. Prepared risk of bias tables, interpreted data and edited the paper. HS. Interpreted data and provided methodological perspective and general advice on the review.

DECLARATIONS OF INTEREST None.

SOURCES OF SUPPORT

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Internal sources • Chris Hani Baragwanath Hospital, Johannesburg, South Africa. • Guy’s, King’s & St Thomas’ School of Medicine, King’s College Hospital, UK.

External sources • Cochrane Heart Group Fellowship for Developing Countries, UK.

INDEX TERMS Medical Subject Headings (MeSH) Anti-Inflammatory Agents [∗ therapeutic use]; Aspirin [therapeutic use]; Immunoglobulins, Intravenous [therapeutic use]; Myocarditis [∗ drug therapy]; Randomized Controlled Trials as Topic; Rheumatic Heart Disease [∗ drug therapy]; Steroids [therapeutic use]

MeSH check words Humans

Anti-inflammatory treatment for carditis in acute rheumatic fever (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Anti-inflammatory treatment for carditis in acute rheumatic fever.

Rheumatic heart disease remains an important cause of acquired heart disease in developing countries. Although prevention of rheumatic fever and manag...
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