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Minimal Clinically Important Difference for Six-minute Walk Test in Patients with HFrEF and Iron Deficiency

Open AccessPublished:November 01, 2022DOI:https://doi.org/10.1016/j.cardfail.2022.10.423

      Highlights

      • MCIDs for meaningful changes in 6MWT were identified using PGA as a clinical anchor
      • Small changes in 6MWT were shown to be clinically meaningful in patients with HFrEF
      • These MCIDs may help measure the clinical impact of treatments on exercise capacity
      • These MCIDs may also allow interpretation of study data

      ABSTRACT

      Background

      The six-minute walk test (6MWT) is widely used to measure exercise capacity; however, the magnitude of change that is clinically meaningful for individuals is not well established in heart failure with reduced ejection fraction (HFrEF).

      Objective

      To calculate the minimal clinically important difference (MCID) for change in exercise capacity on the 6MWT in iron-deficient HFrEF populations.

      Methods

      In this pooled secondary analysis of FAIR-HF and CONFIRM-HF trials, mean changes in 6MWT from baseline to weeks 12 and 24 were calculated and calibrated against the Patient Global Assessment (PGA) tool [clinical anchor] to derive MCIDs for improvement and deterioration.

      Results

      Of 760 patients included in the two trials, 6MWT and PGA data were available for 680 (89%) and 656 (86%) patients at weeks 12 and 24, respectively. The mean 6MWT distance at baseline was 281±103m. There was a modest correlation between changes in 6MWT and PGA from baseline to week 12 (r=0.31, p<0.0001) and week 24 (r=0.43, p<0.0001). Respective estimates (95% confidence intervals) for MCID in 6MWT at weeks 12 and 24 were 14m (5;23) and 15m (3;27) for a “little improvement” (vs no change), 20m (10;30) and 24m (12;36) for “moderate improvement” vs a “little improvement”, -11m (-32;9.2) and -31m (-53;-8) for a “little deterioration” (vs no change), and -84m (-144;-24) and -69m (-118;-20) for “moderate deterioration” vs a “little deterioration”.

      Conclusions

      The MCID for improvement in exercise capacity on the 6MWT was 14–15m in patients with HFrEF and iron deficiency. These MCIDs can aid clinical interpretation of study data.

      Keywords

      Nonstandard abbreviations list:

      CONFIRM-HF (Ferric CarboxymaltOse evaluatioN on perFormance in patients with IRon deficiency in coMbination with chronic Heart Failure), FAIR-HF (Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure), FCM (ferric carboxymaltose), GRS (Global Rating Scale), MCID (minimal clinically important difference), PGA (Patient Global Assessment)

      INTRODUCTION

      Impaired functional capacity is common in patients with heart failure (HF) (
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      Improving functional capacity in heart failure: the need for a multifaceted approach.
      ). With increasing focus on patient preference for a better overall health status, in addition to a reduction in use of traditional disease-specific endpoints, such as morbidity and mortality (
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      ), therapeutic targets in patients with HF have expanded to encompass improvements in functional capacity and health status (health-related quality of life) (
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      • et al.
      Prioritizing functional capacity as a principal end point for therapies oriented to older adults with cardiovascular disease: a scientific statement for healthcare professionals from the American Heart Association.
      ). The 6-minute walk test (6MWT) is an indicator of exercise capacity and prognosis in various cardiopulmonary conditions (
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      Triangulating clinically meaningful change in the six-minute walk test in individuals with chronic heart failure: a systematic review.
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      The six-minute walk test predicts peak oxygen uptake and survival in patients with advanced heart failure.
      ). The 6MWT is one of the common instruments used to measure changes in exercise capacity in patients with HF and is increasingly included as a clinical trial endpoint in HF studies (
      • Hamo CE
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      Novel endpoints for heart failure clinical trials.
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      Traditional and new composite endpoints in heart failure clinical trials: facilitating comprehensive efficacy assessments and improving trial efficiency.
      ). However, an understanding of the magnitude of change that is clinically meaningful to the patient (the minimal clinically important difference [MCID]) is fundamental to the interpretation of changes in 6MWT and decision-making regarding the effectiveness of an intervention.
      A wide range of 6MWT MCIDs have been previously reported across different patient populations and studies: in patients with lung diseases, MCIDs ranging from 10 to 80 m have been reported (
      • Polkey MI
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      • et al.
      Six-minute-walk test in chronic obstructive pulmonary disease: minimal clinically important difference for death or hospitalization.
      ,
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      • Nici L.
      The return of the minimum clinically important difference for 6-minute-walk distance in chronic obstructive pulmonary disease.
      ); in patients with pulmonary arterial hypertension, the estimated MCID was approximated at 33 m (
      • Mathai SC
      • Puhan MA
      • Lam D
      • Wise RA.
      The minimal important difference in the 6-minute walk test for patients with pulmonary arterial hypertension.
      ); and in older adults with mobility impairments, the MCID has been estimated at 19 to 22 m (
      • Bohannon RW
      • Crouch R.
      Minimal clinically important difference for change in 6-minute walk test distance of adults with pathology: a systematic review.
      ). In patients with HF specifically, studies have suggested MCIDs ranging from 22 to 90 m (
      • Shoemaker MJ
      • Curtis AB
      • Vangsnes E
      • Dickinson MG.
      Triangulating clinically meaningful change in the six-minute walk test in individuals with chronic heart failure: a systematic review.
      ,
      • Shoemaker MJ
      • Curtis AB
      • Vangsnes E
      • Dickinson MG.
      Clinically meaningful change estimates for the six-minute walk test and daily activity in individuals with chronic heart failure.
      ). This large variation is likely because of the significant heterogeneity in 6MWT distance observed in patients of similar symptomatic presentation (within the same New York Heart Association [NYHA] class) (
      • Yap J
      • Lim FY
      • Gao F
      • Teo LL
      • Lam CS
      • Yeo KK.
      Correlation of the New York Heart Association Classification and the 6-Minute Walk Distance: A Systematic Review.
      ), different study methods, small sample sizes, and proportions of patients lost to follow-up; nevertheless, the MCIDs for 6MWT changes in patients with HF have not been well established.
      In the FAIR-HF (Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure (
      • Anker SD
      • Comin Colet J
      • Filippatos G
      • Willenheimer R
      • Dickstein K
      • Drexler H
      • et al.
      Ferric carboxymaltose in patients with heart failure and iron deficiency.
      )) and CONFIRM-HF (Ferric CarboxymaltOse evaluatioN on perFormance in patients with IRon deficiency in coMbination with chronic Heart Failure (
      • Ponikowski P
      • van Veldhuisen DJ
      • Comin-Colet J
      • Ertl G
      • Komajda M
      • Mareev V
      • et al.
      Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency.
      )) studies, intravenous ferric carboxymaltose (FCM; a nanoparticle iron-carbohydrate complex) improved mean 6MWT distance vs placebo in patients with heart failure with reduced ejection fraction (HFrEF) and iron deficiency. In this analysis, we used an anchor-based approach to establish 6MWT MCIDs in a large, pooled cohort of FAIR-HF and CONFIRM-HF patients, in association with FCM or placebo, using randomised clinical trial data.

      METHODS

      The data for this analysis were drawn from two double-blind, placebo-controlled, parallel-group trials that evaluated the effects of intravenous FCM versus placebo in ambulatory patients with HFrEF and iron deficiency: FAIR-HF (
      • Anker SD
      • Comin Colet J
      • Filippatos G
      • Willenheimer R
      • Dickstein K
      • Drexler H
      • et al.
      Ferric carboxymaltose in patients with heart failure and iron deficiency.
      ) and CONFIRM-HF (
      • Ponikowski P
      • van Veldhuisen DJ
      • Comin-Colet J
      • Ertl G
      • Komajda M
      • Mareev V
      • et al.
      Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency.
      ). The detailed designs and inclusion criteria for these studies have been previously published (
      • Anker SD
      • Colet JC
      • Filippatos G
      • Willenheimer R
      • Dickstein K
      • Drexler H
      • et al.
      Rationale and design of Ferinject assessment in patients with IRon deficiency and chronic Heart Failure (FAIR-HF) study: a randomized, placebo-controlled study of intravenous iron supplementation in patients with and without anaemia.
      ,
      • Ponikowski P
      • van Veldhuisen DJ
      • Comin-Colet J
      • Ertl G
      • Komajda M
      • Mareev V
      • et al.
      Rationale and design of the CONFIRM-HF study: a double-blind, randomized, placebo-controlled study to assess the effects of intravenous ferric carboxymaltose on functional capacity in patients with chronic heart failure and iron deficiency.
      ), with key study characteristics shown in Table 1. The trials were approved by the appropriate regulatory authorities and ethics committees at each participating centre, and all patients who participated in the individual randomised controlled trials provided written informed consent. The trials were conducted in strict compliance with the guidelines for Good Clinical Practice of the International Council for Harmonization and with the Declaration of Helsinki.
      Table 1Key characteristics of the two included randomised controlled trials
      FAIR-HF (
      • Anker SD
      • Comin Colet J
      • Filippatos G
      • Willenheimer R
      • Dickstein K
      • Drexler H
      • et al.
      Ferric carboxymaltose in patients with heart failure and iron deficiency.
      ,
      • Anker SD
      • Colet JC
      • Filippatos G
      • Willenheimer R
      • Dickstein K
      • Drexler H
      • et al.
      Rationale and design of Ferinject assessment in patients with IRon deficiency and chronic Heart Failure (FAIR-HF) study: a randomized, placebo-controlled study of intravenous iron supplementation in patients with and without anaemia.
      )
      CONFIRM-HF (
      • Ponikowski P
      • van Veldhuisen DJ
      • Comin-Colet J
      • Ertl G
      • Komajda M
      • Mareev V
      • et al.
      Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency.
      ,
      • Ponikowski P
      • van Veldhuisen DJ
      • Comin-Colet J
      • Ertl G
      • Komajda M
      • Mareev V
      • et al.
      Rationale and design of the CONFIRM-HF study: a double-blind, randomized, placebo-controlled study to assess the effects of intravenous ferric carboxymaltose on functional capacity in patients with chronic heart failure and iron deficiency.
      )
      Randomisation2:1 (FCM:placebo)1:1 (FCM:placebo)
      Number of patients459 (FCM: 304; placebo: 155)301
      304 patients were randomised, but only 301 received study treatment and had any post-baseline assessment. 6MWT = 6-minute walk test; CHF = chronic heart failure; CONFIRM-HF = Ferric CarboxymaltOse evaluatioN on perFormance in patients with IRon deficiency in coMbination with chronic Heart Failure; FAIR-HF = Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure; FCM = ferric carboxymaltose; HF = heart failure; NYHA = New York Heart Association; PGA = Patient Global Assessment.
      (FCM: 150; placebo: 151)
      Study duration24 weeks52 weeks
      Patient population and HF detailsAmbulatory patients with optimally treated CHF (NYHA class II/III) and iron deficiencyAmbulatory patients with optimally treated CHF (NYHA class II/III) and iron deficiency
      Haemoglobin≥9.5 and ≤13.5 g/dL<15 g/dL
      Primary endpointChange in PGA score and NYHA class from baseline to week 24Change in 6MWT distance from baseline to week 24
      low asterisk 304 patients were randomised, but only 301 received study treatment and had any post-baseline assessment. 6MWT = 6-minute walk test; CHF = chronic heart failure; CONFIRM-HF = Ferric CarboxymaltOse evaluatioN on perFormance in patients with IRon deficiency in coMbination with chronic Heart Failure; FAIR-HF = Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure; FCM = ferric carboxymaltose; HF = heart failure; NYHA = New York Heart Association; PGA = Patient Global Assessment.

      Assessment of Exercise Capacity Measurements

      The 6MWT is a submaximal exercise test that involves measuring distance walked over a span of 6 minutes. Participants were encouraged to walk on a straight, flat surface as fast as possible for 6 minutes on a marked course, with pauses as necessary. The maximum distance walked was recorded and used to estimate exercise capacity (6MWT) at baseline and weeks 4, 12, and 24 in FAIR-HF, and at baseline and weeks 6, 12, 24, 36, and 52 in CONFIRM-HF. For the purpose of this analysis, data from the placebo and treatment arms were pooled from both studies at both the 12- and 24-week time points.

      Assessment of Patient Perceptions of Clinical Change

      The Patient Global Assessment (PGA), a general health-related quality of life tool based on a Likert scale, was administered to evaluate the magnitude of change in patient-perceived HF status compared with the start of treatment using the following response categories: +3 – “much improvement”; +2 – “moderate improvement”; +1 – a “little improvement”; 0 – “no change”, –1 – a “little deterioration”, –2 – “moderate deterioration”, and –3 – “much deterioration”. The English version of the PGA has been translated for clinical use into 14 different languages by professional translators and double-checked by native-speaking Vifor Pharma employees. The PGA was administered at post-randomisation visits before any other interview, assessment, or procedure, and in this analysis, data from the 12- and 24-week time points were pooled from each study.

      Assessment of Minimal Clinically Important Difference

      The MCID for the 6MWT was evaluated using an anchor-based approach that calibrates exercise capacity against a clinically relevant external indicator. PGA, which has been used to assess patient condition as directly perceived by the patient and used in several prior MCID calculations, was chosen as the clinical anchor against which changes in 6MWT were calibrated (
      • Cheung YT
      • Foo YL
      • Shwe M
      • Tan YP
      • Fan G
      • Yong WS
      • Madhukumar P
      • Ooi WS
      • Chay WY
      • Dent RA
      • Ang SF
      • Lo SK
      • Yap YS
      • Ng R
      • Chan A.
      Minimal clinically important difference for the functional assessment of cancer therapy: cognitive function in breast cancer patients.
      ,
      • Revicki D
      • Hays RD
      • Cella D
      • Sloan J.
      Recommended methods for determining responsiveness and minimally important differences for patient-reported outcomes.
      ,
      • Butler J
      • Khan MS
      • Mori C
      • Filippatos GS
      • Ponikowski P
      • Comin-Colet J
      • Roubert B
      • Spertus JA
      • Anker SD.
      Minimal clinically important difference in quality of life scores for patients with heart failure and reduced ejection fraction.
      ). 6MWT mean change scores were calculated for each category of change in PGA to estimate the MCID. Patients with data on PGA and 6MWT at two or more time points were included. The assessment at week 12 was chosen as the key endpoint because it was considered the most appropriate time point to balance the minimum possible time duration required for an intervention to be impactful with recall ability and the risk of patient attrition and missing data. The assessment at week 24 was used to evaluate the stability of estimates over longer follow-up durations.

      Statistical Analysis

      Data were reported as number (%) for categorical variables and mean (standard deviation [SD]) for continuous variables. Patients were stratified by PGA category (much improvement, moderate improvement, a little improvement, no change, a little deterioration, moderate deterioration, and much deterioration) and mean (standard error; SE) change from baseline in 6MWT was calculated for the subgroup of patients in each category. Anchor-based MCIDs with 95% confidence intervals (CIs) for the 6MWT were then calculated by subtracting the mean change from baseline in 6MWT score in one PGA subgroup from that in the adjacent PGA subgroup. For example, the mean change in 6MWT for patients in the “no change” PGA subgroup was subtracted from the mean change in 6MWT for the patients in the “little improvement” PGA subgroup to give the MCID. MCIDs for “moderate” vs “mild” and “much” vs “moderate” improvements and corresponding deteriorations in 6MWT distance were similarly calculated. The influence of the treatment allocation on the MCID was assessed using ANCOVA (Analysis of Co-Variance) of the 6MWT change by PGA classes, treatment groups and the interaction PGA x treatment. A similar ANCOVA model was used to assess if baseline 6MWT (divided in to tertiles) had any influence on MCID.
      Correlations between changes in 6MWT and PGA anchor values from baseline to different time points were calculated using a non-parametric Spearman's rank correlation coefficient to assess the level of confidence in the interpretation of results. The linearity of the association between the analysed 6MWT changes (continuous scale) and PGA at weeks 12 and 24 was assessed by analysing residuals of the linear regression of each score by PGA.
      Patients with a missing baseline 6MWT value and/or who did not have ≥1 post-baseline 6MWT and/or PGA value prior to the time point of interest were excluded from all analyses. Patients who died or were hospitalised during the time period of interest were excluded from the main analysis, as were patients who did not have values for PGA or 6MWT at each of the specific 12- and 24-week time points. For the sensitivity analysis, patients with missing data who were known to be alive and not hospitalised were imputed using the last observation carried forward (LOCF), while patients who died or were hospitalised were categorised as having experienced “much deterioration” for the PGA analysis, and improvement in 6MWT for such patients was considered zero metres for that specific time point. Two-tailed p-values were used for all correlation and regression assessments, with p<0.05 considered statistically significant. SAS version 9.4 (SAS Institute, Inc., Cary, NC, USA; 2000–2004) was used to conduct all analyses.

      RESULTS

      Of the 760 patients in the pooled FAIR-HF and CONFIRM-HF population, 6MWT change from baseline data were available for 684 (90%) and 660 (87%) patients at weeks 12 and 24, respectively, while PGA data were available for 685 (90%) and 669 (88%) patients at weeks 12 and 24, respectively. Overall, 680 patients had a baseline 6MWT value and non-missing values for both PGA and 6MWT at week 12 and 656 patients had a baseline 6MWT value and non-missing values for both PGA and 6MWT at week 24; these patients were included in the main MCID analysis. The sensitivity analysis with imputation for death, hospitalisation and LOCF included 738 and 739 patients at weeks 12 and 24, respectively. A flow diagram delineating patients included in main and sensitivity analyses is shown in Supplementary Figure 1.
      The mean (SD) age of the 760 patients was 68 (10) years, 51% were female, and 67% were in NYHA class III. Almost all patients (>99%) were from a White/European ethnic background. The mean distance recorded for the 6MWT at baseline was 281±103 m. Table 2 summarises the pooled baseline and clinical characteristics of participants enrolled across the two studies.
      Table 2Pooled baseline and clinical characteristics of the included patients
      FCM pool (n = 454)Placebo pool (n = 306)Total (n = 760)
      Age, years67.8 (10.1)68.2 (10.4)68.0 (10.2)
      Female sex226 (49.8)159 (52.0)385 (50.7)
      White European ethnicity452 (99.6)305 (99.7)757 (99.6)
      NYHA class III321 (70.7)186 (60.8)507 (66.7)
      LVEF, %33.6 (6.7)34.7 (6.9)34.1 (6.8)
      BMI, kg/m228.1 (4.7)28.6 (5.4)28.3 (5.0)
      6MWT distance, m278.6 (102.8)285.1 (104.2)281.2 (103.3)
      Comorbidities
      Hypertension373 (82.2)259 (84.6)632 (83.2)
      Diabetes mellitus131 (28.9)82 (26.8)213 (28.0)
      Smoking133 (29.3)82 (26.8)215 (28.3)
      Atrial fibrillation493 (53.9)431 (57.7)924 (55.6)
      Prior MI500 (54.7)395 (52.9)895 (53.9)
      Prior stroke99 (10.8)103 (13.8)202 (12.2)
      Prior coronary revascularisation312 (34.1)278 (37.2)590 (35.5)
      Hb, g/dL12.1 (1.3)12.2 (1.4)12.1 (1.3)
      Hb category
      <10 g/dL26 (5.7)12 (3.9)38 (5.0)
      ≥10 and <12 g/dL181 (39.9)120 (39.2)301 (39.6)
      ≥12 g/dL247 (54.4)174 (56.9)421 (55.4)
      Serum ferritin, ng/mL54.0 (52.6)58.6 (55.6)55.9 (53.8)
      Serum ferritin category
      <50 ng/mL266 (58.6)172 (56.2)438 (57.6)
      ≥50 and <100 ng/mL138 (30.4)95 (31.1)233 (30.7)
      ≥100 ng/mL50 (11.0)39 (12.8)89 (11.7)
      TSAT, %18.5 (14.5)17.4 (8.3)18.1 (12.4)
      TSAT category
      ≤10%94 (20.7)61 (19.9)155 (20.4)
      >10 and ≤20%213 (46.9)140 (45.8)353 (46.5)
      >20%147 (32.4)105 (34.3)252 (33.2)
      eGFR, mL/min/1.73 m264.4 (20.8)64.2 (22.5)64.3 (21.5)
      eGFR <60 mL/min/1.73 m2179 (39.4)137 (44.8)316 (41.6)
      Ischaemic HF etiology370 (81.5)249 (81.4)619 (81.4)
      Concomitant medication
      ARNI or SGLT2 inhibitor0 (0.0)0 (0.0)0 (0.0)
      ACEI or ARB or ARNI423 (93.2)283 (92.5)706 (92.9)
      Beta-blocker393 (86.6)267 (87.3)660 (86.8)
      Aldosterone antagonists237 (52.2)147 (48.0)384 (50.5)
      Triple therapy194 (42.7)122 (39.9)316 (41.6)
      Values are mean (SD) for continuous variables and n (%) for categorical variables. 6MWT = 6-minute walk test; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor-neprilysin inhibitor; BMI = body mass index; CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; eGFR = estimated glomerular filtration rate; FCM = ferric carboxymaltose; Hb = haemoglobin; LVEF = left ventricular ejection fraction; MI, myocardial infarction; NYHA = New York Heart Association; SD = standard deviation; TSAT = transferrin saturation.

      Correlation between Change in 6MWT Distance and PGA Score

      There were statistically significant but modest correlations between change in 6MWT and PGA score from baseline to week 12 (r = 0.31, p <0.0001) and week 24 (r = 0.43, p <0.0001) [Supplementary Figure 2 and 3]. For changes in 6MWT at weeks 12 and 24, no substantial deviations from a normal distribution were detected, with low correlations with PGA (expressed as deterioration and improvement).

      Mean Change in 6MWT Distance Across PGA Categories

      The distributions of patients across the seven PGA categories (from much improvement to much deterioration) at weeks 12 and 24 are shown in Figure 1 and the mean changes in 6MWT distance within each of these PGA categories at weeks 12 and 24 are shown in Figure 2. At week 12, 45 patients (7%) had experienced “much improvement”, 162 (24%) had experienced “moderate improvement”, 223 (33%) had experienced “little improvement”, and 221 (32%) had experienced “no change” in PGA score vs baseline. The mean (SE) change in 6MWT distance was 57 m (10) for those with “much improvement” in PGA score, 45 m (4) for those with “moderate improvement” in PGA score, 26 m (3) for those with a “little improvement” in PGA score, and 12 m (3) for those with “no change” in PGA score; results were similar at week 24 (Figure 2).
      Figure 1
      Figure 1Patient distribution across PGA categories at weeks 12 and 24
      Caption: The figure shows the percentage of patients (N=760) in each of the PGA categories at week 12 and week 24. The PGA categories (much improvement, moderate improvement, a little improvement, no change, a little deterioration, moderate deterioration, and much deterioration) are coded according to the colour legend shown in the figure. No imputation was performed in this analysis. HFrEF = heart failure with reduced ejection fraction; PGA = Patient Global Assessment.
      Figure 2
      Figure 2Mean change in 6MWT across PGA categories at weeks 12 and 24
      Caption: The figure shows the mean (SE) change in 6MWT distance from baseline to week 12 and week 24 in each PGA subgroup (much improvement, moderate improvement, a little improvement, no change, a little deterioration, moderate deterioration, and much deterioration) coded according to the colour legend shown in the figure. No imputation was performed in this analysis. 6MWT = 6-minute walk test; PGA = Patient Global Assessment; SE, standard error.
      At week 12, 26 patients (4%) had experienced “little deterioration” in PGA score vs baseline and 8 patients (1%) had experienced “moderate deterioration”, with no patients experiencing “much deterioration”; these results were similar at week 24 (Figure 1). The mean (SE) change in 6MWT distance was 1 (10) for those with “little deterioration” and –84 (43) for those with moderate deterioration in PGA score at week 12; corresponding values at week 24 were –19 m (8) and –87 m (36), respectively (Figure 2).

      Estimates of Minimal Clinically Important Difference

      The results of the 6MWT MCID main, treatment subset, and sensitivity analyses at weeks 12 and 24 are shown in Table 3. Using PGA as the clinical anchor, the MCID (95% CI) for “little improvement” (vs “no change”) in 6MWT in the main analysis was 14 m (5;23) at week 12 and 15 m (3;27) at week 24, and the MCID for “little deterioration” (vs “no change”) was –11 m (–32;9) at week 12 and –31 m (–53;–8) at week 24. The estimated MCID (95% CI) for “moderate improvement” vs “little improvement” was 20 m (10;30) at week 12 and 24 m (12;36) at week 24, while the MCID for ‘moderate deterioration’ vs “little deterioration” was -84 m (-144;-24) at week 12 and –69 m (–118;-20) at week 24. The estimated MCID for “much improvement” vs “moderate improvement” was 12 m (–8;31) at week 12 and 13 m (–2;28) at week 24. Estimates of the MCID for “much deterioration” vs “moderate deterioration” could not be calculated due to a lack of patients with “much deterioration” in PGA score at either time point. Results of the sensitivity analysis including patients who died or were hospitalised and using imputations are also shown in Table 3.
      Table 3MCID for improvement and deterioration in 6MWT at weeks 12 and 24
      MCID (95% CI), m
      ImprovementDeterioration
      PGA subgroupsLittle (vs no change)Moderate (vs little)Much (vs moderate)Little (vs no change)Moderate (vs little)Much (vs moderate)
      Main analysis
      Week 1213.8 (5.1; 22.5)19.7 (9.7; 29.6)11.6 (–7.6; 30.7)–11.1 (–31.5; 9.2)–84.2 (–144.0; -24.3)N/A
      Week 2415.0 (3.4; 26.7)24.2 (12.4; 36.0)13.4 (–1.7; 28.4)–30.8 (–53.2; –8.4)-68.8 (–117.9; –19.8)N/A
      FCM subset analysis
      Week 1217.7 (6.0; 29.4)20.7 (8.2; 33.2)14.9 (-7.2; 37.2)-28.8 (-56.8; -0.6)-81.6 (-167.1; 3.8)N/A
      Week 2420.1 (4.4; 35.8)22.2 (9.0; 35.7)15.4 (-3.0; 33.8)-11.9 (-53.4; 29.6)-94.5 (-191.2; 2.1)N/A
      Placebo subset analysis
      Week 125.9 (-7.4; 19.1)3.8 (-11.6; 19.3)6.3 (-26.8; 39.3)2.9 (-26.2; 32.0)-86.6 (-177.9; 4.8)N/A
      Week 245.3 (-12.2; 22.8)15.7 (-7.7; 39.1)10.1 (-10.8; 31.1)-40.7 (-65.5;-15.9)-53.0 (-110.1; 3.9)N/A
      Sensitivity analysis
      Including imputation for patients who died or were hospitalised (categorised as having experienced “much deterioration” for the PGA analysis and zero metres for improvement in 6MWT; note: the method for handling of deaths and hospitalisations when computing MCID is not well established) and last observation carried forward for patients known to be alive and not hospitalised with baseline and ≥1 post-baseline value. N=CI = confidence interval; 6MWT = 6-minute walk test; MCID = minimal clinically important difference; N/A = not available; PGA, patient global assessment.
      Week 1214.1 (5.6; 22.5)18.2 (8.5; 27.9)18.2 (–1.6; 38.0)–11.6 (–31.3; 8.2)–73.1 (–129.0; –17.3)–154.0 (–274.5; –33.6)
      Week 2416.9 (5.8; 27.9)23.3 (11.9; 34.8)16.7 (0.9; 32.4)–25.4 (–46.9; –3.9)–60.2 (–106.9; –13.6)–169.1 (–247.3; –90.9)
      low asterisk Including imputation for patients who died or were hospitalised (categorised as having experienced “much deterioration” for the PGA analysis and zero metres for improvement in 6MWT; note: the method for handling of deaths and hospitalisations when computing MCID is not well established) and last observation carried forward for patients known to be alive and not hospitalised with baseline and ≥1 post-baseline value. N=CI = confidence interval; 6MWT = 6-minute walk test; MCID = minimal clinically important difference; N/A = not available; PGA, patient global assessment.
      On assessing the significance of treatment allocation on the MCID, none of the interactions were found to be statistically significant (P-values for little improvement vs no change, moderate improvement vs little improvement, much improvement vs moderate improvement, little deterioration vs no change and moderate deterioration vs little deterioration were 0.19, 0.13, 0.69, 0.13 and 0.93 respectively at week 12. For week 24, P-values were 0.21, 0.61, 0.75, 0.22 and 0.40 respectively) but a clear scale effect was observed with a larger difference between the PGA classes in the FCM group compared to placebo. Similarly, no statistically significant interaction was seen on analyzing the influence of baseline tertiles (<240m [n=244], 240-<321m [n=262] and >321m [n=253]) of 6MWT on MCID (P-values for little improvement vs no change, moderate improvement vs little improvement, much improvement vs moderate improvement, little deterioration vs no change and moderate deterioration vs little deterioration were 0.15, 0.22, 0.16, 0.32 and 0.47 respectively at week 12. For week 24, P-values were 0.71, 0.77, 0.67, 0.25 and 0.30 respectively). However, a scale effect was observed with patients who had lower baseline distance showing higher improvement.

      DISCUSSION

      In this pooled analysis of patients with HFrEF and iron deficiency, we report two key findings. First, MCID estimates for “little improvement” vs “no change” in 6MWT among patients with HFrEF and iron deficiency were 14 and 15 m at weeks 12 and 24, respectively. This suggests that even small changes in 6MWT are clinically meaningful, with the MCID for improvement remaining largely similar between the two time points studied. Second, MCID estimates for “little deterioration” in 6MWT among patients with HFrEF and iron deficiency were –11 m and –31 m at weeks 12 and 24, respectively. These results suggest that, in contrast to improvements, the MCID for deterioration may become greater and more difficult to achieve over longer follow-up durations. Together, these results have clinical implications because data on MCID in distance walked during the 6MWT can aid clinicians and researchers in establishing therapeutic thresholds that are objective, measurable, and patient-centred. These, in turn, can be used to assess the efficacy of interventions for improving exercise capacity among patients with HFrEF and iron deficiency.

      Comparison with MCIDs observed in other analyses

      Compared with previous studies that used the Global Rating Scale (GRS) as a clinical anchor to investigate MCIDs for the 6MWT in patients with HF, the MCID estimates observed in our analysis of study patients with HFrEF and iron deficiency were lower (
      • O'Keeffe ST
      • Lye M
      • Donnellan C
      • Carmichael DN.
      Reproducibility and responsiveness of quality of life assessment and six minute walk test in elderly heart failure patients.
      ,
      • Spertus J
      • Peterson E
      • Conard MW
      • Heidenreich PA
      • Krumholz HM
      • Jones P
      • et al.
      Monitoring clinical changes in patients with heart failure: a comparison of methods.
      ); using a 15-point GRS collapsed to seven levels as a clinical-based anchor, Spertus et al. reported an estimate of 55 m for moderate improvement over a 6-week time period (
      • Revicki D
      • Hays RD
      • Cella D
      • Sloan J.
      Recommended methods for determining responsiveness and minimally important differences for patient-reported outcomes.
      ), compared with 34 m at 12 weeks in this study; using a 5-point GRS, O'Keeffe et al. found clinically meaningful changes of 43 m to correspond with “little improvement” at 4-week follow-up (
      • O'Keeffe ST
      • Lye M
      • Donnellan C
      • Carmichael DN.
      Reproducibility and responsiveness of quality of life assessment and six minute walk test in elderly heart failure patients.
      ), in contrast to 14 m at 12 weeks observed here. However, these prior studies were limited by small sample sizes and a large proportion of patients were lost to follow-up.
      It should also be noted that MCIDs are not universal and cannot be used to compare different patient populations (
      • Wright A
      • Hannon J
      • Hegedus EJ
      • Kavchak AE.
      Clinimetrics corner: a closer look at the minimal clinically important difference (MCID).
      ); rather, MCIDs are more contextual, depending on various factors such as baseline characteristics and demographics, disease severity, the clinical anchor used, and calculation methods (
      • Wright A
      • Hannon J
      • Hegedus EJ
      • Kavchak AE.
      Clinimetrics corner: a closer look at the minimal clinically important difference (MCID).
      ,
      • Lauridsen HH
      • Hartvigsen J
      • Manniche C
      • Korsholm L
      • Grunnet-Nilsson N.
      Responsiveness and minimal clinically important difference for pain and disability instruments in low back pain patients.
      ,
      • Copay AG
      • Subach BR
      • Glassman SD
      • Polly Jr, DW
      • Schuler TC.
      Understanding the minimum clinically important difference: a review of concepts and methods.
      ). This may have accounted for the lower MCIDs observed in the current analysis of patients with HFrEF and iron deficiency. In this analysis, the MCIDs for deterioration were –11 m and –31 m at weeks 12 and 24, respectively, indicating that even small deteriorations in 6MWT distance can be clinically meaningful. However, it should be noted that in patients with HFrEF, 6MWT distance is an independent predictor of poorer survival and a greater likelihood of hospitalisation (
      • Matsumoto K
      • Xiao Y
      • Homma S
      • Thompson JLP
      • Buchsbaum R
      • Ito K
      • et al.
      Prognostic impact of 6 min walk test distance in patients with systolic heart failure: insights from the WARCEF trial.
      ). Therefore, patients who have already experienced even small deteriorations in their condition and have achieved a correspondingly shorter 6MWT distance may be at risk of poorer outcomes; this, rather than just the degree of change in 6MWT distance, needs to be taken into account. To the best of our knowledge, this is the first study to report estimates of MCID for improvement and deterioration of 6MWT in patients with HFrEF and iron deficiency (with or without anaemia) using clinical trial data. It is also important to emphasize that while “little improvement” has generally been considered MCID, other authors have used varying thresholds such as “moderate improvement” to define MCID. These differences exist because of the different perceptions of what is “clinically meaningful”. The clinically meaningful thresholds may vary based on several factors such as invasiveness and cost of the intervention.

      Magnitudes of MCID across the spectrum of improvements and deteriorations

      We found that the MCIDs for “little improvement” (vs “no change”), “moderate improvement” (vs “little improvement”), and for “much improvement” (vs “moderate improvement”) in 6MWT were consistent and ranged from 12 to 20 m between categories. Moreover, it is important to note that the MCID for “little improvement” (vs no change) remained relatively stable between weeks 12 and 24 (14 and 15 m, respectively), indicating that improvements may remain stable over longer follow-ups. In contrast, the MCID for “little deterioration” (vs no change) showed a decrease between weeks 12 and 24 (–11 and –31 m, respectively). We also observed that the MCID for “moderate deterioration” (vs “little deterioration”) was much larger than that for “moderate improvement” (vs “little improvement”), indicating that it may be relatively easier to achieve a moderate clinically meaningful improvement in functional capacity compared with a moderate clinically meaningful deterioration. Future studies should evaluate MCIDs for improvements and deteriorations for longer follow-up periods to assess stability, and adjust for measured interventions.

      Use of MCIDs when interpreting clinical trial data

      Interpretation of future clinical trials such as HEART-FID (Randomized Placebo Controlled Trial of Ferric Carboxymaltose as Treatment of Heart Failure with Iron Deficiency) can be based on the MCIDs presented in this study (
      • Mentz RJ
      • Ambrosy AP
      • Ezekowitz JA
      • Lewis GD
      • Butler J
      • Wong YW
      • De Pasquale CG
      • Troughton RW
      • O'Meara E
      • Rockhold FW
      • Garg J
      • Samsky MD
      • Leloudis D
      • Dugan M
      • Mundy LM
      • Hernandez AF
      HEART-FID Trial Investigators. Randomized Placebo-Controlled Trial of Ferric Carboxymaltose in Heart Failure With Iron Deficiency: Rationale and Design.
      ). For instance, the proportion of patients who experience clinically meaningful changes in health in response to treatments can be reported. In addition, the reported thresholds can be used to categorise patients as responders or non-responders in terms of improvement or deterioration in clinical status, which can then be used to compare the effectiveness of treatments at an individual patient level, to establish the minimum number of patients needed to treat to detect clinically relevant changes, and to measure the stability of the response. Provided that an adequate safety margin is considered, clinically relevant improvements in exercise capacity may also be used as a measure in the approval process for new therapeutic agents (
      • Zannad F
      • Garcia AA
      • Anker SD
      • Armstrong PW
      • Calvo G
      • Cleland JGF
      • et al.
      Clinical outcome endpoints in heart failure trials: a European Society of Cardiology Heart Failure Association consensus document.
      ). Future studies should include other interventions to further establish MCIDs for improvement and deterioration in patients with HFrEF.

      Study limitations

      There are several limitations in this study. Firstly, generalisability is limited because the patient population mainly consisted of white, adult HFrEF (predominantly NYHA class III) patients with iron deficiency (with or without anaemia). For patients with different ethnic backgrounds, preserved ejection fraction, more or less severe NYHA class, and HF without iron deficiency, different MCIDs may apply. Secondly, this analysis only assessed changes over a relatively short period at 12 to 24 weeks; some of the interventions employed, such as interdisciplinary care, may benefit from longer follow-ups. Thirdly, approximately 60% of the patients in this analysis received intravenous FCM; iron repletion in patients with initial iron deficiency may specifically increase functional capacity and perceived quality of life by separate mechanisms. Nevertheless, pooling data from FCM and placebo arms to calculate MCID allowed inclusion of subjects across the whole range of PGA categories, with exploratory, non-significant differences between FCM and placebo arms reflecting high variability across subjects in the subjective PGA endpoint. Fourthly, while the 6MWT is a simple, low-cost test with good reliability, peak oxygen consumption (peak VO2) is considered the gold-standard for assessing aerobic capacity (
      • Ross RM
      • Murthy JN
      • Wollak ID
      • Jackson AS.
      The six minute walk test accurately estimates mean peak oxygen uptake.
      ). However, peak VO2 is expensive and not easy to measure, and was not recorded in FAIR-HF and CONFIRM-HF trials. It was measured in the EFFECT-HF study of FCM in HFrEF (
      • van Veldhuisen DJ
      • Ponikowski P
      • van der Meer P
      • Metra M
      • Böhm M
      • Doletsky A
      • et al.
      Effect of ferric carboxymaltose on exercise capacity in patients with chronic heart failure and iron deficiency.
      ) but this study was not included in the present pooled analysis because of its open-label design. Lastly, analysis of MCID for deterioration was based on a small number of patients, and it can be expected that post hoc analyses of clinical trials may favour the responders and survivors.

      CONCLUSIONS

      In conclusion, the MCID for improvement in 6MWT in patients with HFrEF, iron deficiency and a 6MWT distance of 281 m at baseline was 14 m at 12 weeks, suggesting that even small changes in 6MWT can be clinically meaningful. Our findings could be used by clinicians to evaluate the efficacy of specific interventions in improving exercise capacity. Furthermore, these thresholds could be used in sample size calculations in future trials involving patients with HFrEF, aiding in assessing efficacies and thus drug approvals for this population. Further exploration using various clinical anchors, interventions, and calculation methods should be done in future studies to validate and establish the MCID for 6MWT in patients with HFrEF and iron deficiency, with or without anaemia.

      Funding

      The FAIR-HF and CONFIRM-HF trials were funded by Vifor Pharma.

      brief bullet points about how their work applies to patients and lay Summary (<100 words)

      • The six-minute walk test (6MWT, which measures the maximum distance a person can walk in six minutes) is an indicator of exercise capacity; it is important to know what size of change in 6MWT distance over time represents a meaningful change for an individual
      • In this study of patients with heart failure and iron deficiency, a 6MWT distance increase of 14 m or more in 12 weeks was shown to represent a meaningful improvement, while a decrease of 31 meters or more represented a meaningful worsening
      • These findings could be used by doctors to evaluate whether certain treatments may provide a patient with meaningful improvements in exercise capacity
      This analysis combined data from two studies in patients with heart failure and iron deficiency. A patient survey was used to measure quality of life and the six-minute walk test (6MWT) was used to measure exercise capacity. Authors investigated what magnitude of change in 6MWT distance corresponded with a meaningful change in quality of life. Results showed that a 6MWT distance increase of 14 m or more in 12 weeks represented a meaningful improvement, while a decrease of 31 meters or more represented a meaningful worsening. These findings could be used to help doctors interpret the results of clinical studies.

      Visual Take Home graphic

      Caption: illustration of the MCID thresholds representing clinically meaningful changes in 6MWT at week 12 in patients with HFrEF and iron deficiency. No imputation was included in this analysis. 6MWT, six-minute walk test; HFrEF, heart failure with reduced ejection fraction; MCID, minimally clinically important difference.

      Conflict of interest statements

      SDA has received research grants and personal fees from Vifor Int and Abbott Vascular (IIT/Trial steering committee work); personal fees from Bayer, Boehringer Ingelheim and Impulse Dynamics (Trial steering committee work), Novartis, Cardiac Dimensions and Occlutech (Adivsory committee work), Servier (Registry Steering Committee). TF reports support for statistical consultancies and personal fees from Vifor for the present manuscript; consulting fees for statistical consultancies and personal fees from Bayer, CSL Behring, Galapagos, Minoryx, Vifor, Novartis and LivaNova outside of the current work; payment for educational events from Fresenius Kabi outside of the current work; personal fees from Novartis, Eli Lilly and co, Bayer, BiosenseWebster, Janssen, Roche, and Enanta for participation on a Data Safety Monitoring Board. EAJ has received research grants and personal fees from Vifor Pharma (co-PI of the AFFIRM trial); personal fees from Bayer, Novartis, Abbott, Boehringer Ingelheim, Pfizer, Servier, AstraZeneca, Berlin Chemie, Cardiac Dimensions, Fresenius, Respicardia, Takeda, Swixx Biopharma and Gedeon Richter; treasurer of the Executive Committee for the Heart Failure Association. MM has received personal fees from Vifor Pharma (Executive Committee member), Amgen (Executive Committee member and National PI), AstraZeneca, Abbott vascular, Bayer (participation in Advisory Boards), Boehringer Ingelheim (advisory board member), Servier (participation in Advisory Boards and speeches at sponsored symposia), Edwards Therapeutics (speeches at sponsored symposia), Actelion (DMC Member), LivaNova (Executive Committee member), and Windtree Therapeutics (Executive Committee member and Advisory Board). ILP reports personal fees from Boehringer Ingelheim, outside the submitted work. AJSC reports personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Menarini, Novartis, Nutricia, Servier, Vifor, Abbott, Actimed, Arena, Cardiac Dimensions, Corvia, CVRx, Enopace, ESN Cleer, Faraday, Gore, Impulse Dynamics, and Respicardia, outside the submitted work. BR, UMG and FD are full-time employees of Vifor Pharma. JCC reports unrestricted grants from Vifor Pharma and Novartis; consulting fees from Vifor Pharma, AstraZenica and Boehringer Ingelheim; and honoraria for conference activities from Vifor Pharma, AstraZenica and Boehringer Ingelheim. GSF reports grants from the European Commission; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bayer and Boehringer Ingelheim; participation on a data safety monitoring board or advisory board from Bayer and Boehringer Ingelheim; leadership or fiduciary role in the Heart Failure Association; and other financial or non-financial interests as a Committee Member for Medtronic, Vifor Pharma, Amgen, Servier, and Novartis. PP reports participation in clinical trials for and grants and personal fees from Vifor Pharma during the conduct of the study; participation in clinical trials for and personal fees from Amgen, Bayer, Novartis, AbbottVascular, Boehringer Ingelheim, Pfizer, Servier, Astra Zeneca, Cibiem, BMS, and Impulse Dynamics, outside the submitted work; participation in clinical trials for Cardiac Dimensions, outside the submitted work; and personal fees from Berlin Chemie, outside the submitted work. JB reports personal consulting fees from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, G3 Pharma, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Sequana Medical, and Vifor Pharma; and payment for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, BI-Lilly, Janssen, and Novartis. DJVV, GR and MSK have no conflicts of interest relating to the performance of this research or in the evaluation and publication process of the manuscript.

      Acknowledgements

      The authors acknowledge assistance with language editing, formatting, preparation of figures and submission provided by Helen Sims (AXON Communications), funded by Vifor Pharma.

      Appendix. Supplementary materials

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