Health-Related Quality of Life Scores: Ending the Minimum 5-Point Difference as the Clinically Meaningful Threshold

This article refers to ‘Minimal clinically important difference in quality of life scores for patients with heart failure and reduced ejection fraction’ by J. Butler et al., published in this issue on pages 999–1005. Heart failure (HF) patients experience diminished health status, including reductions in physical activity and health-related quality of life (HRQoL). HRQoL scores have been used as endpoints and intermediate prognostic markers in HF trials.1 In HF with reduced ejection fraction (HFrEF), an improvement in HRQoL points towards a beneficial treatment effect.1 The impact of HRQoL improvements in HF with preserved ejection fraction (HFpEF) has been harder to assess due to the lack of trials with a convincingly positive result. In the case of the Kansas City Cardiomyopathy Questionnaire (KCCQ; on which the overall score ranges from 0 to 100, with a higher score indicating a better quality of life), a 5-point change in the overall score has been considered to be a clinically meaningful difference in the health status of the patient.2 In the FAIR-HF trial,3 459 symptomatic HFrEF patients with iron deficiency were randomly assigned to receive intravenous iron (ferric carboxymaltose) or saline (placebo). The primary endpoints were the self-reported Patient Global Assessment (PGA) and New York Heart Association functional class at 24 weeks; HRQoL assessed by the KCCQ was a secondary endpoint. Intravenous ferric carboxymaltose improved symptoms, functional capacity, and HRQoL. In the PGA, a general HRQoL tool based on a Likert scale (on which patients can classify their status as much improved, moderately improved, a little improved, unchanged, a little worse, moderately worse, or much worse/dead), 50% of patients in the ferric carboxymaltose group reported that they felt much or moderately improved, as compared with 28% of patients in the placebo group (odds ratio for being in a better rank 2.51, 95% confidence interval 1.75–3.61; P < 0.001). The KCCQ score started around 53 points in both treatment groups and improved by 14 points in the ferric carboxymaltose group and by 6 points in the placebo group, which gave a treatment effect difference of +7 points in favour of ferric carboxymaltose (P < 0.001). In this issue of the Journal, Butler et al.4 asked and interesting research question which is what are the magnitudes of change in KCCQ that are clinically important to patients (as assessed by the PGA) to determine the minimal clinically important differences (MCID) as a patient-centred measure. The correlations between the PGA and the KCCQ were fair and most KCCQ domain scores had a less than 5-point MCID for ‘little improvement’, suggesting that KCCQ changes of smaller magnitude than the traditional 5-point threshold may be clinically meaningful, which may be relevant for the interpretation of patient-reported outcomes and for the endpoint selection in future HF trials. Looking into other recent HF drug trials, a similar pattern is observed. For example, in the PARADIGM-HF trial, sacubitril/valsartan (vs. enalapril) improved KCCQ by (‘only’) +1.3 points5; still, treatment with sacubitril/valsartan resulted in a 20% relative reduction of HF hospitalizations or cardiovascular death.6 In the DAPA-HF trial, dapagliflozin (vs. placebo) improved KCCQ by +2.8 points and reduced HF hospitalizations or cardiovascular death by 26%.7 Improvements of ±1 point in KCCQ were also observed in TOPCAT and PARAGON-HF, which were HFpEF trials with marginal treatment effects in favour of spironolactone and sacubitril/valsartan (vs. placebo and valsartan), respectively, with marked internal heterogeneity, as elsewhere discussed.8-10 The association between the KCCQ score changes and subsequent clinical outcomes was studied in the HF-ACTION trial, where a non-linear relationship between change in KCCQ and outcomes was found with any increment up to 8 points and any decrease being associated with better and worse outcomes, respectively.11 Findings that support the notion that improvements below 5 points are clinically relevant. In HF patients, physical limitation, daily activities, obesity, non-cardiac comorbid conditions, social and psychological factors may have a major impact in HRQoL and not necessarily be improved by a cardiovascular treatment.12 Moreover, HF is a chronic disease that inexorably will deteriorate with aging. Hence, if a given HF drug is capable of, at least, stabilize or provide little improvement (vs. a placebo or active control) to a patient's quality of life that's already a lot to ask for a pill. Therefore, a threshold <5 points in HRQoL should be considered as clinical meaningful. In a trial, this can be assessed with a binary outcome with ‘1’ indicating an ‘event’ when any HRQoL deterioration is observed. When assessing HRQoL the totality of events should also be incorporated that is, patients that were hospitalized or died before the HRQoL evaluation should be considered in the analysis; this can be achieved by using statistical techniques such as the ‘win ratio’13 (Table 1). In conclusion, small changes in HRQoL should be considered as clinically meaningful, providing that patients who were hospitalized or died before the HRQoL assessment are considered for the analysis. Conflict of interest: none declared.