National Institute for Health and Care Excellence Consultation Rheumatoid arthritis in adults: diagnosis and management Evidence review F DMARDs NICE guideline CG79 Intervention evidence review January 08 Consultation This evidence review was developed by the National Guideline Centre
Contents Disclaimer The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and, where appropriate, their carer or guardian. Local commissioners and providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties. NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn. Copyright
Contents Contents First line DMARDs... 7. Review questions:... 7 In adults with Rheumatoid Arthritis (RA) who are DMARD naïve, which conventional DMARDs (alone or combined) are most clinically and cost effective?... 7 In adults with RA who are DMARD naïve, which DMARD treatment strategy (monotherapy, sequential monotherapy, parallel combination therapy, step up therapy or step down therapy) is most clinically and cost effective?... 7. Introduction... 7.3 PICO table... 7.4 Clinical evidence... 8.4. Included studies... 8.4. Summary of clinical studies included in the evidence review... 9.4.3 Quality assessment of clinical studies included in the evidence review... 4.5 Economic evidence... 4.5. Included studies... 4.5. Excluded studies... 4.5.3 Summary of studies included in the economic evidence review... 43.5.4 Unit costs... 46.6 Resource costs... 46.7 Evidence statements... 46.7. Clinical evidence statements... 46.7. Health economic evidence statements... 49.8 Recommendations... 49 Further treatment after first line DMARD treatment failure... 60. Review questions:... 60 In adults with RA who have had an inadequate response to, or failed treatment with, one or more conventional DMARDs, which conventional DMARDs (alone or combined) are most clinically and cost effective as subsequent treatments?... 60 In adults with RA who have had an inadequate response to, or failed treatment with, one or more conventional DMARDs, which DMARD treatment strategy (monotherapy, sequential monotherapy, parallel combination therapy, step up therapy or step down therapy) is most clinically and cost effective as subsequent treatment?... 60. Introduction... 60.3 PICO table... 60.4 Methods and process... 6.5 Clinical evidence... 6.5. Included studies... 6.5. Excluded studies... 6.5.3 Summary of clinical studies included in the evidence review... 6.5.4 Quality assessment of clinical studies included in the evidence review... 65 4
Contents.6 Economic evidence... 70.6. Included studies... 70.6. Excluded studies... 70.6.3 Unit costs... 70.7 Resource costs... 7.8 Evidence statements... 7.8. Clinical evidence statements... 7.8. Health economic evidence statements... 7.9 Recommendations... 7... 8 Appendices... 97 Appendix A: Review protocols... 97 Appendix B: Literature search strategies... 06 B. Health Economics literature search strategy... 0 Appendix C: Clinical evidence selection... 5 Appendix D: Clinical evidence tables... 7 D.. First line DMARDs... 7 D.. Failed DMARDs... 83 Appendix E: Forest plots... 98 E. First line DMARDs... 98 E.. Monotherapy: sulfasalazine (SSZ) versus placebo... 98 E.. Monotherapy: hydroxychloroquine (HCQ) versus placebo... 98 E..3 Monotherapy: sulfasalazine (SSZ) versus monotherapy methotrexate (MTX)... 99 E..4 Monotherapy: leflunomide (LFN) versus monotherapy: methotrexate (MTX)... 00 E..5 Monotherapy: hydroxychloroquine (HCQ) versus monotherapy: sulfasalazine (SSZ)... 0 E..6 Monotherapy: hydroxychloroquine (HCQ) versus monotherapy: methotrexate (MTX)... 0 E..7 Step-down therapy: sulfasalazine (SSZ), methotrexate (MTX) versus monotherapy: sulfasalazine (SSZ)... 0 E..8 Parallel combination therapy: methotrexate (MTX), sulfasalazine (SSZ) versus monotherapy: sulfasalazine (SSZ)... 04 E..9 Parallel combination therapy: methotrexate (MTX), sulfasalazine (SSZ) versus monotherapy: methotrexate (MTX)... 04 E..0 Parallel combination therapy: methotrexate (MTX), sulfasalazine (SSZ), hydroxychloroquine (HCQ) versus monotherapy: methotrexate (MTX)... 06 E.. Parallel combination therapy: methotrexate (MTX), sulfasalazine (SSZ), hydroxychloroquine (HCQ) versus monotherapy: sulfasalazine (SSZ)... 06 E.. Step up therapy: methotrexate (MTX), sulfasalazine (SSZ), 5
Contents hydroxychloroquine (HCQ) versus sequential monotherapy: methotrexate (MTX), sulfasalazine (SSZ), leflunomide (LFN)... 07 E..3 Parallel combination therapy: sulfasalazine (SSZ), hydroxychloroquine (HCQ) versus parallel combination therapy: methotrexate (MTX), hydroxychloroquine (HCQ)... 07 E..4 Step up therapy: sulfasalazine (SSZ), methotrexate (MTX), hydroxychloroquine (HCQ) versus parallel combination therapy: methotrexate (MTX), sulfasalazine (SSZ), hydroxychloroquine (HCQ)... 07 Poor prognosis subgroup... 08 E..5 Parallel combination therapy: methotrexate (MTX), leflunomide (LFN) versus parallel combination therapy: methotrexate (MTX), sulfasalazine (SSZ)... 08 E..6 Step up therapy: methotrexate (MTX), leflunomide (LFN) versus parallel combination therapy: methotrexate (MTX), sulfasalazine (SSZ)... 09 E..7 Step up therapy: methotrexate (MTX), leflunomide (LFN) versus parallel combination therapy: methotrexate (MTX), leflunomide (LFN)... 0 E. Failed DMARDs... E.. Step-up therapy (sulfasalazine plus leflunomide (SSZ plus LEF)) versus sequential monotherapy (sulfasalazine (SSZ) plus placebo) in people who failed leflunomide monotherapy... E.. Step-up therapy (methotrexate plus sulfasalazine (MTX plus SSZ)) versus sequential monotherapy (methotrexate (MTX)) in people who failed sulfasalazine monotherapy... E..3 Step-up therapy (methotrexate plus sulfasalazine then methotrexate plus sulfasalazine plus hydroxychloroquine) versus sequential monotherapy (sulfasalazine then leflunomide) in people who failed methotrexate monotherapy... 3 Appendix F: GRADE tables... 5 F. First line DMARDs... 5 F. Failed DMARDs... 38 Appendix G: Health economic evidence selection... 44 Appendix H: Health economic evidence tables... 46 H. First line DMARDs... 46 H. Failed DMARDs... 5 Appendix I: Excluded studies... 5 I. Excluded health economic studies... 57 Appendix J: Research recommendations... 59 6
First line DMARDs First line DMARDs. Review questions: 3 4 5 6 7 8 9 0 In adults with Rheumatoid Arthritis (RA) who are DMARD naïve, which conventional DMARDs (alone or combined) are most clinically and cost effective? In adults with RA who are DMARD naïve, which DMARD treatment strategy (monotherapy, sequential monotherapy, parallel combination therapy, step up therapy or step down therapy) is most clinically and cost effective?. Introduction 3 4 5 6 7 8 DMARDs suppress disease activity and slow down radiological progression in rheumatoid arthritis, resulting in symptom improvement and reduced long-term disability. There are several conventional DMARDs that can either be prescribed as stand-alone monotherapy or combined. Treatment strategies include monotherapy, sequential monotherapy, parallel combination therapy, step-up therapy, and step-down therapy. At present it is unclear which DMARD or which DMARD treatment strategy is the most effective, both for newly diagnosed rheumatoid arthritis and further treatment..39 PICO table 0 For full details see the review protocol in appendix A. Table : PICO characteristics of review question Population Adults with RA who are DMARD naïve. Studies in adults with poor prognostic factors will be presented separately. Interventions methotrexate (oral) (MTX oral) methotrexate (subcutaneous) (MTX sc) hydroxychloroquine (HCQ) sulfasalazine (SSZ) leflunomide (LFN) combinations of the above sequential combinations of the above. Study treatment arms will be classified into one of the following classes: monotherapy (a single DMARD used for the duration of the trial) sequential monotherapy (a single DMARD replaced with a different single DMARD in the case of inadequate response) parallel combination (two or more DMARDs commenced at the same time without a step-down strategy) step up (commencing with a single DMARD, followed by the addition of further DMARD(s) in the case of inadequate response) step down (two or more DMARDs commenced at the same time, with at 7
First line DMARDs Comparison Outcomes Study design least one drug tapered and stopped once disease is adequately controlled). The intervention medications can be compared against each other or against placebo. CRITICAL Disease Activity Score (DAS) (continuous) at 6 and months Quality of life (continuous) at 6 and months Function (continuous) at 6 and months IMPORTANT Low disease activity (dichotomous) at 6 and months Remission (dichotomous) at 6 and months ACR50 response (dichotomous) at 6 and months Pain (continuous) at 6 and months Radiological progression (continuous) at months Adverse events mortality (dichotomous) at longest reported time point Withdrawal due to adverse events (dichotomous) at longest reported time point Withdrawal due to inefficacy (dichotomous) at longest reported time point Randomised controlled (RCTs) Systematic Review / Network Meta-Analysis of RCTs 3 4 5 6 Studies that enrol people who are not explicitly reported to be DMARD naïve will be excluded, except where: the study states that the only DMARD used previously is an antimalarial or hydroxychloroquine (as hydroxychloroquine is known to be a weak DMARD); or previous DMARDs have been used for no longer than month. These populations will be included on the basis that they would not differ substantially from a DMARD naïve population in terms of disease severity or likely response to DMARD treatment..4 7 Clinical evidence.4. 8 Included studies 9 0 3 4 5 6 7 8 9 0 3 4 5 6 7 An existing Cochrane review 59,60 by Hazelwood et al. comparing methotrexate monotherapy with methotrexate in combination with other DMARDs formed the basis of the evidence review. The included studies in that review were checked for inclusion in this evidence review based on the agreed evidence review protocol. Searches were also conducted for randomised controlled and systematic reviews as follows: the Cochrane review search strategy was re-run to identify relevant published since the date of the Cochrane review searches; and a search was conducted to identify additional of non-methotrexate monotherapies and combinations that would not have been included in the Cochrane review. This was not date limited. Twenty-one studies were included in the review;,5,7,77 these are summarised in Table. Evidence from these studies is summarised in the clinical evidence summaries below in Table 3 - Table 9. 6,7,3,,7,8,3,33,40,46,48,55,57,68,96,08,8,37 The included studies covered 7 comparisons across a range of monotherapy, sequential monotherapy, parallel combination therapy, step-down therapy and step up therapy treatment regimens compared against each other and in some cases against placebo. No evidence was found for subcutaneous methotrexate. See also the study selection flow chart in appendix C, study evidence tables in appendix D, forest plots in appendix E and GRADE tables in appendix H. 8
First line DMARDs See the excluded studies list in appendix I..4. Summary of clinical studies included in the evidence review 3 Table : Summary of randomised controlled included in the evidence review Intervention and Study comparison Population Outcomes Comments Monotherapy versus placebo Anonymous 99 7 Monotherapy: sulfasalazine versus placebo People with RA for less than months and no evidence of erosions in hands or feet N= Pain Withdrawal: adverse events Withdrawal: inefficacy High dose medication in intervention arm. Short term glucocorticoid treatment not used. Anonymous 995 6 Monotherapy: hydroxychloroquine versus placebo Adults with RA for less than years. Persistent synovitis despite treatment with aspirin or NSAIDs. N=0 Function Pain Quality of life Withdrawal: adverse events Withdrawal: inefficacy High dose medication in intervention arm. Short term glucocorticoid treatment used. Clark 993 Monotherapy: hydroxychloroquine versus placebo Adults with active RA and 5 years since diagnosis and unsuccessful treatment with + NSAIDs or salicylates. N=6 Pain High dose medication in intervention arm. Short term glucocorticoid treatment usage unclear. Davis 99 7 Monotherapy: hydroxychloroquine versus placebo People with RA and palpable synovitis in the hands, wrists or feet N=04 Withdrawal: inefficacy High dose medication in intervention arm. Short term glucocorticoids not used. Hannonen 993 57 Monotherapy: sulfasalazine versus placebo People with active RA with disease symptoms for < months. N=80 Radiological progression Adverse events - mortality High dose medication in intervention arm. Short term glucocorticoids used. Monotherapy versus monotherapy Ferraccioli 00 40 Monotherapy: sulfasalazine versus monotherapy: methotrexate People aged 7-70 with active RA and at least erosion and 4 month course of antimalarials. N=84 ACR50 response High dose medication in both arms. Short term glucocorticoids used. Considered indirect evidence due to previous course of 9
First line DMARDs Study Jaimeshernandez 0 68 Lisbona mp 0 96 Nuverzwart 989 8 Van jaarsveld 000 7 Intervention and comparison Population Outcomes Comments antimalarials. Combination therapy of both interventions given to nonresponders after 6 months. Monotherapy: leflunomide versus monotherapy: methotrexate Monotherapy: leflunomide versus monotherapy: methotrexate Monotherapy: hydroxychloroquine versus monotherapy: sulfasalazine Monotherapy: hydroxychloroquine versus monotherapy: methotrexate Adults with active RA. N=85 Monotherapy versus other treatment class COBRA trial: Boers 997 3 Step-down therapy: sulfasalazine and methotrexate versus monotherapy: sulfasalazine People with early RA: symptom duration for less than year. N=78 People aged 6-75 years old with definite or classical and active RA. N=60 People with RA. Disease duration for less than year. N=3 Adults with active RA and disease duration years N=56 Disease Activity Score (DAS8) Function ACR50 response Remission Withdrawal: adverse events Withdrawal: inefficacy Disease Activity Score (DAS8) Function Pain Pain Pain Radiological progression Withdrawal: adverse events Withdrawal: inefficacy Function ACR remission Pain Withdrawal: adverse events Withdrawal: inefficacy Disease Activity Score (DAS) Function Function Remission ACR50 response Pain Pain Withdrawal: Low dose medication in both arms. Short term glucocorticoids used. 3% had prior DMARD treatment and had washout period. Committee agreed this percentage would not affect overall results. High dose medication. Short term glucocorticoids used. High dose medication in both arms. Short term glucocorticoids not used. High dose medication in both arms. Short term glucocorticoids not used. Medications changed if adverse events made discontinuation inevitable. Mixed dose level in arm and high dose study in high dose in arm. Short term glucocorticoid treatment used. Excluded patients previously or currently treated with DMARDs except antimalarials. 0
First line DMARDs Study Intervention and comparison Population Outcomes Comments adverse events Withdrawal: inefficacy den Uyl 04 3 Parallel combination therapy: methotrexate and sulfasalazine versus monotherapy Methotrexate. Adults with active RA. Disease duration for years or less. N=64 Disease Activity Score (DAS) Function ACR Remission ACR50 response Pain Withdrawal: adverse events Withdrawal: inefficacy High dose medication in both arms. Short term glucocorticoids used. Both arms given a regular dose of prednisone. Sequential change to parenteral methotrexate considered in group though only utilised in 4% of participants. Dougados 999 33 3 treatment arms: Parallel combination therapy: methotrexate and sulfasalazine versus monotherapy: sulfasalazine versus monotherapy methotrexate People with active RA. Disease duration less than year. N=09 Withdrawal: adverse events Withdrawal: inefficacy High dose medication in all arms. Short term glucocorticoids not used. FIN-RACo trial: Mottonen 999 08 Parallel combination therapy: sulfasalazine and methotrexate and hydroxychloroquine versus monotherapy: sulfasalazine Adults with active RA and symptom duration < years. N=99 Remission Withdrawal: adverse events Withdrawal: inefficacy Low dose medication in arm and high dose medication in arm. Short term glucocorticoids used. Haagsma 997 55 3 treatment arms: Parallel combination therapy: methotrexate and sulfasalazine versus monotherapy: sulfasalazine versus monotherapy: methotrexate Adults with active RA with disease duration less than year. N=05 Disease Activity Score (DAS) Disease Activity Score (DAS) Function Pain Pain Withdrawal: adverse events Withdrawal: adverse events Withdrawal: inefficacy High dose medication in all arms. Short term glucocorticoids used. If dose was not effective after 4 weeks in study then participant withdrawn from study. Placebos utilised for blinding. Tascioglu 003 5 Parallel combination therapy: methotrexate and sulfasalazine versus monotherapy: methotrexate Adults with active RA and disease duration for less than year. N=70 Function Pain Withdrawal: adverse events Withdrawal: adverse events Low dose medication. Short term glucocorticoids not used. Participants excluded from the study if
First line DMARDs Study treach trial: de Jong 03 8 Intervention and comparison Population Outcomes Comments treatment not effective after weeks or if serious adverse events occurred. Parallel combination therapy: methotrexate and sulfasalazine and hydroxychloroquine versus monotherapy: methotrexate Adults with arthritis of or more joints for less than year. Results extracted for those with RA via 987 ACR criteria. N=89 Comparison of non-monotherapy treatment classes BeSt study: Goekoop- Ruiterman 005 48 3 treatment arms: Step up therapy: methotrexate then add sulfasalazine then add hydroxychloroquine, then biologic DMARD combinations versus parallel combination therapy: methotrexate and sulfasalazine. Then step-up to biologic DMARD combinations versus sequential monotherapy: methotrexate to sulfasalazine to leflunomide, followed by biologic DMARD combinations. Adults with active RA and disease duration years N=380 Disease Activity Score (DAS) Function a Pain Remission Function Radiological progression High dose medication. Short term glucocorticoids used. Outcomes only extracted at time points prior to people beginning biologic treatment. Outcomes only extracted at time points prior to people beginning biologic treatment. Participants DMARD naïve (other than antimalarials - 9%). High dose medication in all intervention arms. Short term glucocorticoid treatment used in arms and 3. First two treatment arms are effectively methotrexate monotherapy for 6 months and outcomes extracted on that basis. Ghosh 008 46 Parallel combination therapy: sulfasalazine and hydroxychloroquine versus parallel combination therapy: methotrexate and hydroxychloroquine People with RA with disease duration for less than 6 months. N=0 Disease Activity Score (DAS8) Remission Low dose medication in both arms. Short term glucocorticoids not used. Saunders 008 37 Step up therapy: sulfasalazine then methotrexate then hydroxychloroquine versus parallel combination therapy: methotrexate and sulfasalazine and hydroxychloroquine People aged 8 to 80 with active RA N=96 Disease Activity Score (DAS8) Quality of life Function at months Low disease activity Remission High dose medication in both arms. Short term glucocorticoids used. No previous DMARD treatment except for hydroxychloroquine.
First line DMARDs Study Intervention and comparison Population Outcomes Comments Poor-prognosis disease strata Verschuere n 06 77 3 treatment arms: Step up therapy: methotrexate then leflunomide versus parallel combination therapy: methotrexate and leflunomide versus parallel combination therapy: methotrexate and sulfasalazine People with RA with disease duration year. Defined as "high risk" due to erosions, rheumatoid factor, ACPA, disease activity. N=89 ACR50 response Pain Radiological progression Withdrawal: adverse events Disease Activity Score (DAS8) Disease Activity Score (DAS8) Function Function Low disease activity Low disease activity Remission Remission Radiological progression Withdrawal: adverse events Withdrawal: inefficacy High dose in arms and 3, mixed dose in arm. Short term glucocorticoids used. Some participants took biologic medications outside of treatment protocol. Numbers range from % to 0% depending on treatment group. See appendix D for full evidence tables. 3 4 3
First line DMARDs 4.4.3 Quality assessment of clinical studies included in the evidence review.4.3. Monotherapy versus placebo 3 Table 3: Clinical evidence summary: monotherapy: sulfasalazine (SSZ) compared to placebo No of Anticipated absolute effects Participa Relati nts Quality of ve (studies) the effect Follow evidence (95% Outcomes up (GRADE) CI) Risk with Placebo Disease Activity Score at 6 or months - not reported Quality of life at 6 or months - not reported Function at 6 or months - not reported Pain at 6 months VAS. Scale from: 0 to 00. Radiological progression at + months Modified Sharp score. Scale from: 0 to 3 or 64. - - - - - - - - - - - - - - - 65 ( study) 6 months 73 ( study) 44-60 weeks Adverse events - mortality 78 ( study) 48 weeks VERY LOW, due to risk of bias, LOW, due to risk of bias, VERY LOW, due to risk of bias, RR.05 (0.07 to 6.4) The mean pain (VAS) at 6 months in the control groups was 8.8 The mean radiological progression (modified Sharp score) at + months in the control groups was 7. Risk difference with Monotherapy: SSZ (95% CI) The mean pain (VAS) at 6 months in the intervention groups was 8.9 lower (9.07 lower to.7 higher) The mean radiological progression (modified Sharp score) at + months in the intervention groups was 3.6 lower (8. lower to.0 higher) 5 per 000 more per 000 (from 3 fewer to 38 more)
First line DMARDs 5 Outcomes No of Participa nts (studies) Follow up Withdrawal: adverse events 05 ( study) 6 months Withdrawal: inefficacy 05 ( study) 6 months Quality of the evidence (GRADE) LOW due to risk of bias VERY LOW, due to risk of bias, Relati ve effect (95% CI) RR 3.43 (. to 9.75) RR 0.39 (0.08 to.93) Anticipated absolute effects Risk with Placebo Risk difference with Monotherapy: SSZ (95% CI) 77 per 000 87 more per 000 (from 6 more to 673 more) 96 per 000 59 fewer per 000 (from 88 fewer to 89 more) Downgraded by increment if the majority of the evidence was at high risk of bias, and downgraded by increments if the majority of the evidence was at very high risk of bias Downgraded by increment if the confidence interval crossed one MID or by increments if the confidence interval crossed both MIDs Table 4: Clinical evidence summary: monotherapy: hydroxychloroquine (HCQ) compared to placebo No of Anticipated absolute effects Participa Relati nts ve (studies) Quality of effect Follow the evidence (95% Risk difference with Monotherapy: Outcomes up (GRADE) CI) Risk with Placebo HCQ (95% CI) Disease Activity Score at 6 or months - not reported Quality of life at months Global well being. Change score in SD units. - - - - - 5 ( study) 9 months MODERATE due to The mean change in quality of life (global well being) at months in the control groups was 0.0 The mean change in quality of life (global well being) at months in the intervention groups was 0.5 lower (0.89 to 0.5 lower)
First line DMARDs 6 Outcomes Quality of life at 6 months - not reported Function at months Psychological disability via AIMS. Change score in SD units No of Participa nts (studies) Follow up Quality of the evidence (GRADE) Relati ve effect (95% CI) Anticipated absolute effects Risk with Placebo - - - - - 5 ( study) 9 months HIGH The mean change in function (psychological disability via AIMS) at months in the control groups was -0.4 Function at 6 months - not reported - - - - - Pain at 6 months Change in VAS. Scale from: 0 to 00. ( study) 6 months Withdrawal: adverse events 00 ( study) 9 months Withdrawal: inefficacy 5 ( studies) 0 months VERY LOW, due to risk of bias, VERY LOW, due to risk of bias, LOW, due to risk of bias, RR 0.43 (0.04 to 4.55) RR 0.43 (0.3 to 0.8) The mean change in pain (VAS) at 6 months in the control groups was -6.5 Risk difference with Monotherapy: HCQ (95% CI) The mean change in function (psychological disability via AIMS) at months in the intervention groups was 0.03 lower (0.39 lower to 0.33 higher) The mean change in pain (VAS) at 6 months in the intervention groups was 9.3 lower (30. to 8.38 lower) 43 per 000 5 fewer per 000 (from 4 fewer to 54 more) 6 per 000 49 fewer per 000 (from 5 fewer to 0 fewer) Downgraded by increment if the confidence interval crossed one MID or by increments if the confidence interval crossed both MIDs Downgraded by increment if the majority of the evidence was at high risk of bias, and downgraded by increments if the majority of the evidence was at very high risk of bias
First line DMARDs 7.4.3. Monotherapy versus monotherapy 3 Table 5: Clinical evidence summary: monotherapy sulfasalazine (SSZ) compared to monotherapy: methotrexate (MTX) No of Relati Anticipated absolute effects Participa ve nts Quality of the effect (studies) evidence (95% Risk difference with Monotherapy: Outcomes Follow up (GRADE) CI) Risk with Monotherapy MTX SSZ (95% CI) Disease Activity Score at months Change in DAS. Scale from: 0 to 0 Disease Activity Score at 6 months Change in DAS. Scale from: 0 to 0 Quality of life at 6 or months - not reported Function at months Change in HAQ. Scale from: 0 to 3. Function at 6 months - not reported 55 ( study) months 55 ( study) 3 months VERY LOW, due to risk of bias, VERY LOW, due to risk of bias, The mean change in Disease Activity Score (DAS) at months in the control groups was - The mean change in Disease Activity Score (DAS) at 6 months in the control groups was - - - - - 55 ( study) months ACR50 response at 6 months 79 ( study) 6 months VERY LOW, due to risk of bias, The mean change in function (HAQ) at months in the control groups was -0.46 - - - - VERY LOW,,3 due to risk of bias,, RR 0.66 (0.4 to.08) The mean change in Disease Activity Score (DAS) at months in the intervention groups was 0. higher (0.4 lower to 0.8 higher) The mean change in Disease Activity Score (DAS) at 6 months in the intervention groups was 0. lower (0.38 lower to 0.8 higher) The mean change in function (HAQ) at months in the intervention groups was 0.4 higher (0.6 lower to 0.44 higher) 57 per 000 94 fewer per 000 (from 337 fewer to 46 more) Pain at months 55 The mean change in pain (VAS) at The mean change in pain (VAS) at
First line DMARDs 8 Outcomes Change in VAS. Scale from: 0 to 00. Pain at 6 months Change in VAS. Scale from: 0 to 00. No of Participa nts (studies) Follow up ( study) months 55 ( study) 3 months Withdrawal: adverse events 84 ( studies) months Withdrawal: inefficacy 7 ( studies) months Quality of the evidence (GRADE) VERY LOW, due to risk of bias, VERY LOW, due to risk of bias, VERY LOW, due to risk of bias, VERY LOW, due to risk of bias, Relati ve effect (95% CI) RR.3 (. to 4.8) RR.6 (0.8 to 5.74) Anticipated absolute effects Risk with Monotherapy MTX months in the control groups was -5 The mean change in pain (VAS) at 6 months in the control groups was - Risk difference with Monotherapy: SSZ (95% CI) months in the intervention groups was 0. lower (3.7 lower to 3.5 higher) The mean change in pain (VAS) at 6 months in the intervention groups was 5.8 lower (5.53 lower to 3.93 higher) 94 per 000 more per 000 (from 9 more to 358 more) 54 per 000 63 more per 000 (from 0 fewer to 58 more) Downgraded by increment if the majority of the evidence was at high risk of bias, and downgraded by increments if the majority of the evidence was at very high risk of bias Downgraded by increment if the confidence interval crossed one MID or by increments if the confidence interval crossed both MIDs 3 Downgraded for : all patients had previously received at least a 4 month course of antimalarials Table 6: Clinical evidence summary: monotherapy: leflunomide (LFN) compared to monotherapy: methotrexate (MTX) No of Relati Anticipated absolute effects Participa ve nts Quality of effect (studies) the evidence (95% Risk difference with Monotherapy: Outcomes Follow up (GRADE) CI) Risk with Monotherapy: MTX LFN (95% CI) Disease Activity Score at months 63 ( study) LOW, The mean change in Disease Activity Score (DAS8) at months in the The mean change in Disease Activity Score (DAS8) at months in the
First line DMARDs 9 Outcomes Change in DAS8. Scale from: 0 to 9.4 Disease Activity Score at 6 months Change in DAS8. Scale from: 0 to 9.4 Quality of life at 6 or months - not reported Function at months Change in HAQ-Di. Scale from: 0 to 3. Function at 6 months Change in HAQ. Scale from: 0 to 3. No of Participa nts (studies) Follow up Quality of the evidence (GRADE) months due to risk of bias, 6 ( study) 4 months VERY LOW, due to risk of bias, Relati ve effect (95% CI) Anticipated absolute effects Risk with Monotherapy: MTX control groups was -.93 The mean change in Disease Activity Score (das8) at 6 months in the control groups was -.46 - - - - 63 ( study) months 6 ( study) 4 months DAS remission at months 63 ( study) months Pain at 6 months Change in VAS. Scale from: 0 to 00. 6 ( study) 4 months LOW, due to risk of bias, VERY LOW, due to risk of bias, VERY LOW, due to risk of bias, VERY LOW, due to risk of bias, RR.03 (0.53 to.03) The mean change in function (HAQ- Di) at months in the control groups was -0.44 The mean change in function (HAQ) at 6 months in the control groups was -0.4 Risk difference with Monotherapy: LFN (95% CI) intervention groups was 0.45 higher (0.78 lower to.68 higher) The mean change in Disease Activity Score (das8) at 6 months in the intervention groups was 0.59 higher (0. lower to.9 higher) The mean change in function (HAQ-Di) at months in the intervention groups was 0.9 lower (0.0 to 0.57 lower) The mean change in function (HAQ) at 6 months in the intervention groups was 0.0 higher (0. lower to 0.4 higher) 344 per 000 0 more per 000 (from 6 fewer to 354 more) The mean change in pain (VAS) at 6 months in the control groups was -3 The mean change in pain (VAS) at 6 months in the intervention groups was 3.6 higher (6.09 lower to 3.9 higher) Withdrawal: adverse events 7 RR 59 per 000 04 more per 000
First line DMARDs 0 Outcomes No of Participa nts (studies) Follow up ( study) months Withdrawal: inefficacy 69 ( study) months Quality of the evidence (GRADE) VERY LOW, due to risk of bias, VERY LOW, due to risk of bias, Relati ve effect (95% CI).76 (0.6 to.74) RR 0.55 (0. to.78) Anticipated absolute effects Risk with Monotherapy: MTX Risk difference with Monotherapy: LFN (95% CI) (from 4 fewer to 69 more) per 000 50 fewer per 000 (from 99 fewer to 98 more) Downgraded by increment if the majority of the evidence was at high risk of bias, and downgraded by increments if the majority of the evidence was at very high risk of bias Downgraded by increment if the confidence interval crossed MID or by increments if the confidence interval crossed both MIDs. Table 7: Clinical evidence summary: monotherapy: hydroxychloroquine (HCQ) compared to monotherapy: sulfasalazine (SSZ) No of Anticipated absolute effects Participa Relati nts Quality of ve (studies) the effect Follow evidence (95% Risk difference with Monotherapy: Outcomes up (GRADE) CI) Risk with Monotherapy: SSZ HCQ (95% CI) Disease Activity Score at 6 or months - not reported Quality of life at 6 or months - not reported Function at 6 or months - not reported Pain at months VAS. Scale from: 0 to 00. - - - - - - - - - - - - - - - 57 ( study) 48 weeks VERY LOW, due to risk of The mean pain (VAS) at months in the control groups was 3.8 The mean pain (VAS) at months in the intervention groups was 0. higher (3. lower to 3.6 higher)
First line DMARDs Outcomes Pain at 6 months VAS. Scale from: 0 to 00. Radiological progression at + months Change in SvdH score. Scale from: 0 to 448. No of Participa nts (studies) Follow up 57 ( study) 4 weeks 57 ( study) 48 weeks Withdrawal: adverse events 44 ( study) 48 weeks Withdrawal: inefficacy 5 ( study) 48 weeks Quality of the evidence (GRADE) bias, LOW, due to risk of bias, LOW, due to risk of bias, VERY LOW, due to risk of bias, LOW, due to risk of bias, Relati ve effect (95% CI) RR 0.33 (0.04 to.7) RR.67 (0.8 to 8.7) Anticipated absolute effects Risk with Monotherapy: SSZ The mean pain (VAS) at 6 months in the control groups was 3.6 The mean change in radiological progression (SvdH score) at + months in the control groups was 7.3 Risk difference with Monotherapy: HCQ (95% CI) The mean pain (VAS) at 6 months in the intervention groups was 6.4 lower (8.4 lower to 5.6 higher) The mean change in radiological progression (SvdH score) at + months in the intervention groups was 0 higher (. to 8.89 higher) 60 per 000 07 fewer per 000 (from 54 fewer to 74 more) 5 per 000 09 more per 000 (from 3 fewer to 965 more) Downgraded by increment if the majority of the evidence was at high risk of bias, and downgraded by increments if the majority of the evidence was at very high risk of bias Downgraded by increment if the confidence interval crossed MID or by increments if the confidence interval crossed both MIDs.
First line DMARDs Table 8: Clinical evidence summary: monotherapy: hydroxychloroquine (HCQ) compared to monotherapy: methotrexate (MTX) Outcomes No of Participa nts (studies) Follow up Quality of the evidence (GRADE) Relativ e effect (95% CI) Anticipated absolute effects Risk with Monotherapy: MTX Risk difference with Monotherapy: HCQ (95% CI) Disease Activity Score at 6 or months - not reported - - - - - Quality of life at 6 or months - not reported - - - - - Function at months Change in HAQ. Scale from: 0 to 3. ( study) months LOW, due to risk of bias, The mean change in function (HAQ) at months in the control groups was -0.4 The mean change in function (HAQ) at months in the intervention groups was 0. higher (0.08 lower to 0.8 higher) Function at 6 months - not reported - - - - - ACR remission at months ( study) months VERY LOW,3,4 due to risk of bias,, RR 0.67 (0.38 to.6) 38 per 000 79 fewer per 000 (from 48 fewer to 38 more) Pain at months Change in VAS. Scale from: 0 to 00. ( study) months VERY LOW, due to risk of bias, The mean change in pain (VAS) at months in the control groups was -4 The mean change in pain (VAS) at months in the intervention groups was 3 higher (4.84 lower to 0.84 higher) Discontinuation of strategy: adverse events ( study) months VERY LOW,,4 due to risk of bias,, Peto OR 0.3 (0.0 to 0.75) 48 per 000 50 fewer per 000 (from 90 fewer to 0 more) 5 Discontinuation of strategy: inefficacy ( study) VERY LOW,,4 RR.36 48 per 000 65 more per 000 (from 7 fewer to 60 more)
First line DMARDs 3 Outcomes No of Participa nts (studies) Follow up months Quality of the evidence (GRADE) due to risk of bias,, Relativ e effect (95% CI) (0.86 to 6.45) Anticipated absolute effects Risk with Monotherapy: MTX Risk difference with Monotherapy: HCQ (95% CI) Downgraded by increment if the majority of the evidence was at high risk of bias, and downgraded by increments if the majority of the evidence was at very high risk of bias Indirect evidence: out of scope drug utilised in the case of adverse reaction 3 Indirect evidence: out of scope drug utilised in the case of adverse reaction and outcome does not use DAS or similar score 4 Downgraded by increment if the confidence interval crossed one MID or by increments if the confidence interval crossed both MIDs 5 Risk difference utilised to calculate absolute effect.4.3.3 Monotherapy versus other treatment class 3 Table 9: Clinical evidence summary: step-down therapy: sulfasalazine (SSZ), methotrexate (MTX) compared to monotherapy: sulfasalazine (SSZ) No of Anticipated absolute effects Participant s Quality of the Relative (studies) evidence effect Risk difference with Step-down Outcomes Follow up (GRADE) (95% CI) Risk with Monotherapy: SSZ therapy: SSZ, MTX (95% CI) Disease Activity Score at months Change in DAS. Scale from: 0 to 0. Disease Activity Score at 6 months Change in DAS. Scale from: 0 to 0. 55 ( study) 56 weeks 55 ( study) 8 weeks MODERATE due to risk of bias LOW, due to risk of bias, The mean change in Disease Activity Score (DAS) at months in the control groups was -.3 The mean change in Disease Activity Score (DAS) at 6 months in the control groups was -.3 The mean change in Disease Activity Score (DAS) at months in the intervention groups was 0. lower (0.5 lower to 0.3 higher) The mean change in Disease Activity Score (DAS) at 6 months in the intervention groups was 0.8 lower (.8 to 0.4 lower)
First line DMARDs 4 Outcomes No of Participant s (studies) Follow up Quality of the evidence (GRADE) Relative effect (95% CI) Anticipated absolute effects Risk with Monotherapy: SSZ Risk difference with Step-down therapy: SSZ, MTX (95% CI) Quality of life at 6 or months - not reported - - - - - Function at months Change in HAQ. Scale from: 0 to 3. 55 ( study) 56 weeks LOW, due to risk of bias, The mean change in function (HAQ) at months in the control groups was -0.6 The mean change in function (HAQ) at months in the intervention groups was 0. lower (0.44 lower to 0.04 higher) Function at 6 months Change in HAQ. Scale from: 0 to 3. 55 ( study) 8 weeks LOW, due to risk of bias, The mean change in function (HAQ) at 6 months in the control groups was -0.6 The mean change in function (HAQ) at 6 months in the intervention groups was 0.5 lower (0.7 to 0.8 lower) Function at months Change in MACTAR. Scale from: 0 to 00 55 ( study) 56 weeks MODERATE due to risk of bias The mean change in function (MACTAR) at months in the control groups was 8 The mean change in function (MACTAR) at months in the intervention groups was lower (3.06 lower to.06 higher) Function at 6 months Change in MACTAR. Scale from: 0 to 00 55 ( study) 8 weeks LOW, due to risk of bias, The mean change in function (MACTAR) at 6 months in the control groups was 7 The mean change in function (MACTAR) at 6 months in the intervention groups was 3 higher (.6 to 4.74 higher) ACR remission at months 6 ( study) 56 weeks VERY LOW,,3 due to risk of bias,, RR 0.7 (0.03 to.49) 54 per 000 39 fewer per 000 (from 5 fewer to 80 more) ACR50 response at 6 months 37 ( study) 8 weeks VERY LOW, due to risk of bias, RR.46 (0.96 to.) 339 per 000 56 more per 000 (from 4 fewer to 40 more)
First line DMARDs 5 Outcomes Pain at months Change in VAS. Scale from: 0 to 00. Pain at 6 months Change in VAS. Scale from: 0 to 00. Withdrawal: adverse events No of Participant s (studies) Follow up 55 ( study) 56 weeks 55 ( study) 8 weeks 39 ( study) 56 weeks Withdrawal: inefficacy 4 ( study) 56 weeks Quality of the evidence (GRADE) MODERATE due to risk of bias LOW, due to risk of bias, VERY LOW, due to risk of bias, MODERATE due to risk of bias Relative effect (95% CI) RR 0.53 (0.8 to.55) RR 0.07 (0.0 to 0.5) Anticipated absolute effects Risk with Monotherapy: SSZ The mean change in pain (VAS) at months in the control groups was -5 The mean change in pain (VAS) at 6 months in the control groups was 0 Risk difference with Step-down therapy: SSZ, MTX (95% CI) The mean change in pain (VAS) at months in the intervention groups was higher (6.98 lower to 0.98 higher) The mean change in pain (VAS) at 6 months in the intervention groups was 4 lower (.68 to 5.3 lower) 5 per 000 59 fewer per 000 (from 0 fewer to 69 more) 00 per 000 86 fewer per 000 (from 96 fewer to 98 fewer) Downgraded by increment if the majority of the evidence was at high risk of bias, and downgraded by increments if the majority of the evidence was at very high risk of bias Downgraded by increment if the confidence interval crossed MID or by increments if the confidence interval crossed both MIDs. 3 Indirect evidence: outcome does not use DAS Table 0: Clinical evidence summary: Parallel combination therapy: methotrexate (MTX), sulfasalazine (SSZ) compared to monotherapy: sulfasalazine (SSZ) No of Relativ Anticipated absolute effects Participa e nts Quality of effect Risk difference with Parallel (studies) the evidence (95% combination therapy: MTX, SSZ Outcomes Follow up (GRADE) CI) Risk with Monotherapy: SSZ (95% CI) Disease Activity Score at 5 The mean change in Disease The mean change in Disease Activity
First line DMARDs 6 Outcomes months Change in DAS. Scale from: 0 to 0 Disease Activity Score at 6 months Change in DAS. Scale from: 0 to 0 Quality of life at 6 or months - not reported Function at months Change in HAQ. Scale from: 0 to 3. Function at 6 months - not reported Pain at months Change in VAS. Scale from: 0 to 00. Pain at 6 months Change in VAS. Scale from: 0 to 00. No of Participa nts (studies) Follow up ( study) months 5 ( study) 3 months Quality of the evidence (GRADE) VERY LOW, due to risk of bias, VERY LOW, due to risk of bias, Relativ e effect (95% CI) Anticipated absolute effects Risk with Monotherapy: SSZ Activity Score (DAS) at months in the control groups was -.8 The mean change in Disease Activity Score (DAS) at 6 months in the control groups was -. - - - - - 5 ( study) months VERY LOW, due to risk of bias, The mean change in function (HAQ) at months in the control groups was -0.3 - - - - - 5 ( study) months 5 ( study) 3 months Withdrawal: adverse events 83 ( studies) 0 months VERY LOW, due to risk of bias, LOW, due to risk of bias, VERY LOW, due to risk of RR.47 (0.79 to The mean change in pain (VAS) at months in the control groups was -5 The mean change in pain (VAS) at 6 months in the control groups was -8 Risk difference with Parallel combination therapy: MTX, SSZ (95% CI) Score (DAS) at months in the intervention groups was 0.5 lower (.5 lower to 0.3 higher) The mean change in Disease Activity Score (DAS) at 6 months in the intervention groups was 0 higher (0.8 lower to 0.8 higher) The mean change in function (HAQ) at months in the intervention groups was 0.9 lower (0.5 lower to 0.4 higher) The mean change in pain (VAS) at months in the intervention groups was 0. higher (4.05 lower to 4.5 higher) The mean change in pain (VAS) at 6 months in the intervention groups was 5 higher (5.08 lower to 5.08 higher) 47 per 000 69 more per 000 (from 3 fewer to 58 more)
First line DMARDs 7 Outcomes No of Participa nts (studies) Follow up Withdrawal: inefficacy 64 ( studies) 0 months Quality of the evidence (GRADE) bias, VERY LOW, due to risk of bias, Relativ e effect (95% CI).75) RR 0.38 (0. to.5) Anticipated absolute effects Risk with Monotherapy: SSZ Risk difference with Parallel combination therapy: MTX, SSZ (95% CI) 7 per 000 78 fewer per 000 (from fewer to 9 more) Downgraded by increment if the majority of the evidence was at high risk of bias, and downgraded by increments if the majority of the evidence was at very high risk of bias Downgraded by increment if the confidence interval crossed one MID or by increments if the confidence interval crossed both MIDs 3 Table : Clinical evidence summary: parallel combination therapy: methotrexate (MTX), sulfasalazine (SSZ) compared to monotherapy: methotrexate (MTX) No of Anticipated absolute effects Participa Relativ nts e (studies) Quality of the effect Risk difference with Parallel Follow evidence (95% combination therapy: MTX, SSZ Outcomes up (GRADE) CI) Risk with Monotherapy: MTX (95% CI) Disease Activity Score at months Change in DAS. Scale from: 0 to 0 Disease Activity Score at 6 months Change in DAS. Scale from: 0 to 0 63 ( study) months 5 ( studies) 4.5 months VERY LOW, due to risk of bias, LOW due to risk of bias The mean change in Disease Activity Score (DAS) at months in the control groups was - The mean change in Disease Activity Score (DAS/DAS44) at 6 months in the control groups was -.59 The mean change in Disease Activity Score (DAS) at months in the intervention groups was 0.3 lower (0.83 lower to 0.3 higher) The mean change in Disease Activity Score (DAS/DAS44) at 6 months in the intervention groups was 0.9 lower (0.4 lower to 0.04 higher)
First line DMARDs 8 Outcomes Quality of life at 6 or months - not reported Function at months Change/final HAQ. Scale from: 0 to 3. Function at 6 months Change/final HAQ. Scale from: 0 to 3. No of Participa nts (studies) Follow up Quality of the evidence (GRADE) Relativ e effect (95% CI) Anticipated absolute effects Risk with Monotherapy: MTX - - - - - 8 ( studies) months 7 ( studies) 6 months ACR remission at 6 months 6 ( study) 6 months ACR50 response at 6 months 6 ( study) 6 months Pain at months Change/final VAS. Scale from: 0 to 00. 8 ( studies) months LOW due to risk of bias MODERATE due to risk of bias VERY LOW,,3 due to risk of bias,, LOW, due to risk of bias, VERY LOW, due to risk of bias, RR 0.8 (0.4 to.58) RR 0.9 (0.7 to.9) The mean change/final function (HAQ) at months in the control groups was 0.89 final HAQ or -0.46 change score The mean change/final function (HAQ) at 6 months in the control groups was 0.9 final HAQ or -0.8 change score Risk difference with Parallel combination therapy: MTX, SSZ (95% CI) The mean change/final function (HAQ) at months in the intervention groups was 0. higher (0.04 to 0.5 higher) The mean change/final function (HAQ) at 6 months in the intervention groups was 0. higher (0.06 to 0.9 higher) 98 per 000 38 fewer per 000 (from 5 fewer to 5 more) 67 per 000 49 fewer per 000 (from 79 fewer to 7 more) The mean change/final pain (VAS) at months in the control groups was 5 final pain or -5 change score The mean change/final pain (VAS) at months in the intervention groups was 0.89 higher (9.0 lower to 0.79 higher) Pain at 6 months 80 The mean change/final pain (VAS) The mean change/final pain (VAS) at
First line DMARDs 9 Outcomes Change/final VAS. Scale from: 0 to 00. No of Participa nts (studies) Follow up (3 studies) 5 months Withdrawal: adverse events 40 (4 studies) 9 months Withdrawal: inefficacy 394 (4 studies) 9 months Quality of the evidence (GRADE) VERY LOW, due to risk of bias, VERY LOW, due to risk of bias, VERY LOW, due to risk of bias, Relativ e effect (95% CI) RR.59 (0.8 to 3.6) RR 0.8 (0.3 to.9) Anticipated absolute effects Risk with Monotherapy: MTX at 6 months in the control groups was 9 final pain or -3 change score Risk difference with Parallel combination therapy: MTX, SSZ (95% CI) 6 months in the intervention groups was 0.5 higher (5.96 lower to 7 higher) 59 per 000 35 more per 000 (from fewer to 7 more) 40 per 000 7 fewer per 000 (from 8 fewer to 48 more) Downgraded by increment if the majority of the evidence was at high risk of bias, and downgraded by increments if the majority of the evidence was at very high risk of bias Downgraded by increment if the confidence interval crossed one MID or by increments if the confidence interval crossed both MIDs 3 Indirect evidence: outcome does not use DAS Table : Clinical evidence summary: parallel combination therapy: methotrexate (MTX), sulfasalazine (SSZ), hydroxychloroquine (HCQ) compared to monotherapy: methotrexate (MTX) No of Relativ Anticipated absolute effects Participa e nts Quality of the effect Risk difference with Parallel (studies) evidence (95% combination therapy: MTX, SSZ, Outcomes Follow up (GRADE) CI) Risk with Monotherapy: MTX HCQ (95% CI) The outcomes reported here are from study with intervention groups which are identical for the purposes of this review. Where possible the data for the identical groups have been combined though the pain outcomes are reported separately due to the use of median (IQR) Disease Activity Score at - - - - -
First line DMARDs 30 Outcomes months - not reported Disease Activity Score at 6 months Change in DAS. Scale from: 0 to 0. Quality of life at 6 or months - not reported Function at months - not reported Function at 6 months Change in HAQ. Scale from: 0 to 3. No of Participa nts (studies) Follow up 80 ( study) 3 months Quality of the evidence (GRADE) LOW, due to risk of bias, Relativ e effect (95% CI) Anticipated absolute effects Risk with Monotherapy: MTX The mean change in Disease Activity Score (DAS) at 6 months in the control groups was -.4 - - - - - - - - - - 53 ( study) 3 months DAS remission at 6 months 80 ( study) 3 months Pain at 6 months Median VAS. Scale from: 0 to 00. 3 ( study) VERY LOW, due to risk of bias, VERY LOW, due to risk of bias, MODERATE, 3 due to risk of bias RR.30 (0.86 to.96) The mean change in function (HAQ) at 6 months in the control groups was -0.4 Risk difference with Parallel combination therapy: MTX, SSZ, HCQ (95% CI) The mean change in Disease Activity Score (DAS) at 6 months in the intervention groups was 0.4 lower (0.55 lower to 0.07 higher) The mean change in function (HAQ) at 6 months in the intervention groups was 0.05 lower (0.3 lower to 0.3 higher) 333 per 000 00 more per 000 (from 47 fewer to 30 more) Pain (VAS) (median (IQR)) in the control group was 35 (8-55) Pain (VAS) (median (IQR)) in the intervention group was (4-5) (median difference: 4 lower in the intervention group.) Pain at 6 months Median VAS. Scale from: 0 to 00. 0 ( study) MODERATE, 3 due to risk of bias Pain (VAS) (median (IQR)) in the control group was 35 (8-55) Pain (VAS) (median (IQR)) was (3-34) in the intervention group (median difference: 3 lower in the intervention group) Downgraded by increment if the majority of the evidence was at high risk of bias, and downgraded by increments if the majority of the evidence was