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  • The minimally important difference and patient acceptable symptom state for the Raynaud's condition score in patients with Raynaud's phenomenon in a large randomised controlled clinical trial

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Clinical and epidemiological research
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The minimally important difference and patient acceptable symptom state for the Raynaud's condition score in patients with Raynaud's phenomenon in a large randomised controlled clinical trial
  1. Puja P Khanna1,
  2. Paul Maranian1,
  3. Jeff Gregory2,
  4. Dinesh Khanna1,3
  1. 1Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA
  2. 2MediQuest Therapeutics, Inc, Bothell, Washington, DC, USA
  3. 3Department of Health Services, School of Public Health, University of California at Los Angeles, Los Angeles, California, USA
  1. Correspondence to Dr Dinesh Khanna, Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, 1000 Veteran Avenue, Rm 32-59 Rehabilitation Building, Los Angeles, CA 90095, USA; dkhanna{at}mednet.ucla.edu

Abstract

Background The Raynaud's condition score (RCS) is a validated outcome measure for Raynaud's phenomenon (RP).

Objective To assess the minimally important difference (MID) and patient acceptable symptom state (PASS) for RCS in patients with RP.

Subjects and methods Patients with active RP (n=162) (mean RCS >25 (0–100 visual analogue scale) participated in a placebo-controlled, crossover randomised clinical trial (RCT). Data from the two treatment groups were combined for this analysis. Retrospective and prospective anchors were administered during the RCT. MID groups were defined as the group who reported being somewhat better (anchor #1) and a one-step change from “unbearable” to “very severe”, etc (anchor #2). Patients were considered to have achieved PASS if they rated their Raynaud's condition as “very mild” or “mild” at the last study visit.

Results The mean age of participants was 48.9 years and the mean baseline RCS was 46.4 points. The RCS change score for the MID improvement group ranged from −13.9 to −14.3 points and PASS estimate was 34.0 points.

Conclusion The MID and PASS estimates for RCS are 14–15 points for improvement and 34 points, respectively, on a 0–100 scale in a large RCT of patients with active RP. This information can aid in interpreting RCS in future RP trials.

https://doi.org/10.1136/ard.2009.107706

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    Introduction

    Raynaud's phenomenon (RP) is a common disorder that affects 3−5% of the general population and approximately 90% of patients with scleroderma.1 2 The Raynaud's condition score (RCS) is a validated outcome measure used to assess the level of difficulty experienced owing to RP each day (anchored from “no difficulty” to “extreme difficulty”).3 4 It is administered either as a visual analogue scale (VAS, 0–100) or on an 11-point Likert scale. Patients complete the scale every day and average scores are taken over a 1- or 2-week period.

    As future clinical trials and observational studies of RP are likely to include the RCS, it is important to estimate the minimally important difference (MID)—the smallest improvement in the score that patients perceive as beneficial and that may lead to a change in the patient's disease management.5 MID assesses the “changed” score (improvement/worsening) at a group level over time. OMERACT has also proposed using a patient acceptable symptom state (PASS), defined as an absolute value beyond which the patients consider themselves well.6 The PASS complements MID as it assesses wellbeing (feeling good) at a certain time point.6

    Our objectives were to estimate the MID and PASS scores for RCS in a large randomised clinical trial (RCT) using two patient-reported anchors.

    Methods

    The primary results of the randomised controlled trial (clinicaltrials.gov number NCT00577304) have not been published. In brief, the study comprised patients (n=162, aged 15–70 years) with active RP as determined by a history of cold sensitivity with pallor or cyanosis of the digits or an observed event by the doctor. More details of the study are provided as online supplementary material.

    Analysis

    For this analysis, the data were pooled and analysed without knowledge of the treatment group. The patients completed the RCS daily and were administered two anchors every week. The MID estimates were assessed using an anchor-based approach.7 Anchor #1 was a retrospective anchor: “Consider all the ways that RP affects you (such as number of attacks, duration of attacks, pain, numbness and tingling). Compared with the 2-week period when you were not using medication, how would you rate your overall Raynaud's disease since the last visit? Much worse, somewhat worse, about the same, somewhat better, or much better.” The minimally changed group was defined as the group who reported being somewhat better or somewhat worse for anchor #1. Anchor #2 was a prospective anchor: “Consider all the ways that Raynaud's phenomenon affects you (such as number of attacks, duration of attacks, pain, numbness and tingling). Since the last visit, how severe was your overall Raynaud's disease? Very mild, mild, somewhat severe, moderately severe, very severe and unbearable.” For anchor #2, the group who had a one-step change from “unbearable” to “very severe” or “very severe” to “moderately severe”, etc, was considered to be the MID group.

    To assess PASS, we assigned patients who considered their Raynaud's condition as “very mild” or “mild” at week 6 (last visit) as achieving the PASS and those who considered their Raynaud's condition as “somewhat severe” to “unbearable” as not achieving PASS. PASS cut-off points were identified with the 75th centile estimation.6 More details of the analyses for MID and PASS are provided as online supplementary material.

    Results

    The mean age of participants was 48.9 years, 80.2% were Caucasian, 92.6% of patients were women and the mean (SD) baseline RCS was 46.4 points (16.6; 0–100 mm; table 1); 45 patients had primary RP and 117 patients had secondary RP.

    View this table:
    Table 1

    Demographics of the participants (n=162)

    The Spearman correlation between the anchor #1 versus change in the RCS was 0.42 (p<0.0001) and between anchor #2 versus change in the RCS was 0.25 (p=0.002). The RCS change score for MID improvement group ranged from −13.9 to −14.3 points and was larger than for the “no change” group (−2.4 to −9.1; figure 1 and table 2). The absolute change for MID improvement group ranged from 13.9% to 14.3% and relative change was 28% to 35%. The MID improvement scores for primary RP were −13.3 to −13.8 points and −14.3 to −14.6 points for secondary RP (figure 1 and online Appendix table A1).

    View this table:
    Table 2

    Minimally important difference (MID) estimates for the RCS VAS (0–100)

    For participants on oral vasodilators, the MID improvement scores were −19.2 to −21.0 points and for those not on vasodilators −7.9 to −11.7 points (figure 1 and online Appendix table A2).

    The number of participants who worsened were too few to reach any definitive conclusions. For anchor #1, MID estimates were consistently smaller at time 2 versus time 1 (online Appendix tables A1 and A2). We chose time 2 for anchor #1 because of the crossover design of the study.

    For analysis involving PASS, patients considered their Raynaud's condition satisfactory if their average RCS was ≤34.0 mm (n=71). For primary and secondary RP, PASS estimates were 32.0 points (n=14) and 42.5 points (n=40), respectively. For participants on oral vasodilators, the PASS estimate was 32.0 points (n=23) and 44.7 points (n=31) for those not on vasodilators.

    We assessed MID scores for improvement and PASS for RCSs stratified by “less severe” Raynaud's condition (RCS <49) and “more severe” group (≥49) at baseline. Patients with “more severe” baseline RCSs required a larger change to be minimally improved (online Appendix table A3). Similarly, patients with “less severe” RCS considered 24.7 (n=45) as achieving PASS, whereas patients with “more severe” RCS considered 46.4 (n=26) as satisfactory.

    Discussion

    RCS is a validated outcome measure for RP3 4 and has been used as the primary outcome measure for clinical trials for RP.3 8 9 We show that a change of 14–15 points (0–100 VAS) is the MID for improvement, and achieving a score of 34 points is the PASS in patients with active RP.

    Prior literature has shown that a change of 10 mm (on a 0–100 VAS) is generally accepted as a MID10 11 and a score of 30–35 mm is PASS.6 Our analyses show that a 14–15-point change is the MID for improvement in this RCT. This may be partly owing to the study design that recruited patients with active RCS (active symptoms and RCS >25) who are likely to improve on active treatment or owing to a “placebo effect”. The higher than usual MID is also reflected by the magnitude of effect size (0.71 to 1.05; visit #1 “somewhat better” and “improve 1” groups; table 2)in this study; previous studies have shown that an effect size 0.20 to 0.50 constitutes a MID.10 12

    Tubach et al6 and Heiberg et al13 assessed PASS estimates for different VAS in osteoarthritis and rheumatoid arthritis and reported estimates between 30 and 35 mm. Although we did not estimate the PASS for RCS using the conventional question that asks a patient to rate their current state as “satisfactory”, our PASS estimate (34 mm) is similar to that in the published literature, providing confidence in our results.

    When we assessed MID at time 2 for anchor #1 (at the crossover period), the MID estimates were smaller than at time 1 for anchors #1 and #2. This is probably owing to a floor effect since the majority of patients had already noticed an improvement in their RP during the first phase of the study (either due to active treatment or a placebo effect). For this analysis, we chose to use MID estimates at time 1 since time 2 estimates were very small and probably not clinically meaningful. In addition, the MID estimates were similar to “no change” group (at time 2) making estimates unreliable.14 Therefore, we chose estimates at time 1.

    Our MID estimates for patients on oral vasodilators were greater than for patients not on vasodilators (figure 1). We were unable to discern the reason for this difference as the mean baseline RCSs were similar in two groups (45.4 on vasodilators vs 46.3 not on vasodilators). Of the 117 patients with secondary RP, 60 (51.2%) were on oral vasodilators.

    As previously noted,6 10 the MID and PASS estimates may depend on the baseline scores. This trend was also seen in our analyses where people with higher baseline scores required a larger change in their RCSs for improvement to be considered as minimally improved and their current state satisfactory. This may be related to again the floor effect (where people near to bottom of the scale are limited by how much they can improve) or may represent difference in interpretation of the scale along the continuum.10

    Although our MID estimates are likely to be applicable in interpreting change in the RCS in active RP, it may be a larger-than-usual estimate in patients with RP who are participating in observational studies, and routine care. Since a single MID estimate is unlikely to be applicable to all patient populations, future studies need to consider MID estimates of RCS in other cohorts.

    Our study has several strengths. Our MID and PASS estimates are based on a large sample size of patients participating in a RCT. Second, we prospectively incorporated anchors with an a priori aim of calculating MID estimates. Our estimates were similar using the prospective and retrospective anchors, giving confidence in our estimates.

    Our study has a few limitations. For this analysis, the RCS was administered as a 0–100 VAS. In the original publication, an 11-point Likert scale (0–10) was used.4 Prior analyses have shown that VAS and Likert responses yield similar results in chronic diseases.15 Second, the RCS was administered on an electronic diary rather than in paper and pencil. Electronic diaries have been found to be reliable and valid when compared with paper diaries16 but, conceivably, might affect the MID estimates.

    In conclusion, the MID estimates for RCS are between 14 and 15 points for improvement on a 0–100 scale (or 1.4 to 1.5 points on a 0–10 VAS) and PASS is 34 points (on a 0–100 VAS) in patients with active RP. This information can aid in interpreting the RCS in ongoing and future RP RCTs.

    PPK was supported by National Institutes of Health Award (T32 AR 053463). DK was supported by National Institutes of Health Award (NIAMS K23 AR053858-01A1) and a New Investigator Grant from the Scleroderma Foundation. The clinical trial was supported by MediQuest Therapeutics, Inc who provided the study drug, underwrote the costs of the trial and participated fully with the investigators in protocol design, analysis and interpretation, but did not influence the decision to submit this manuscript, nor did they in any way contribute or influence the content of the manuscript.

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    Supplementary materials

    • Web Only Data ard.2009.107706

      Files in this Data Supplement:

    Footnotes

    • Competing interests JG is an employee of MediQuest Therapeutics, Inc, sponsor of the clinical trial.

    • Ethics approval Obtained from US IRB.

    • Patient consent Obtained.

    • Provenance and peer review Not commissioned; externally peer reviewed.