Minimal Clinically Important Difference in the 6-minute-walk Distance for Patients with Pulmonary Arterial Hypertension

Abstract

Rationale: The 6-minute-walk distance (6MWD) is an important clinical and research metric in pulmonary arterial hypertension (PAH); however, there is no consensus about what minimal change in 6MWD is clinically significant. Objectives: We aimed to determine the minimal clinically important difference in the 6MWD. Methods: We performed a meta-analysis using individual participant data from eight randomized clinical trials of therapy for PAH submitted to the U.S. Food and Drug Administration to derive minimal clinically important differences in the 6MWD. The estimates were externally validated using the Pulmonary Hypertension Association Registry. We anchored the change in 6MWD to the change in the Medical Outcomes Survey Short Form physical component score. Measurements and Main Results: The derivation (clinical trial) and validation (Pulmonary Hypertension Association Registry) samples were comprised of 2,404 and 537 adult patients with PAH, respectively. The mean ± standard deviation age of the derivation sample was 50.5 ± 15.2 years, and 1,849 (77%) were female, similar to the validation sample. The minimal clinically important difference in the derivation sample was 33 meters (95% confidence interval, 27-38), which was almost identical to that in the validation sample (36 m [95% confidence interval, 29-43]). The minimal clinically important difference did not differ by age, sex, race, pulmonary hypertension etiology, body mass index, use of background therapy, or World Health Organization functional class. Conclusions: We estimated a 6MWD minimal clinically important difference of approximately 33 meters for adults with PAH. Our findings can be applied to the design of clinical trials of therapies for PAH.

Keywords: PAH; individual participant data meta-analysis; minimum important difference; walk test.

Figure 1.

Participant flowchart. (A) Study sample from FDA clinical trials (derivation sample). (B) Study sample from the Pulmonary Hypertension Association Registry (validation sample). 6MWD = 6-minute-walk distance; CTEPH = chronic thromboembolic pulmonary hypertension; FDA = U.S. Food and Drug Administration; PAH = pulmonary arterial hypertension; SF = Short Form.

Figure 2.

Minimal clinically important difference (95% confidence interval) in the 6-minute-walk distance using (A) anchor-based (physical component score change of at least five) and (B) distributional methods. 6MWD = 6-minute-walk distance; PHAR = Pulmonary Hypertension Association Registry; ROC = receiver operating characteristic; SMD = standardized mean difference; SRM = standardized response mean.

Figure 3.

Subgroup 6-minute-walk distance (6MWD) MCID (95% confidence interval) estimates from the derivation (clinical trial) data on the basis of a change in physical component score of five. *Age and baseline 6MWD are analyzed as continuous variables. CHD-PAH = PAH associated with congenital heart disease; CTD-PAH = PAH associated with connective tissue disease; MCID = minimal clinically important difference; PAH = pulmonary arterial hypertension; WHO FC = World Health Organization functional class.

Figure 4.

Subgroup 6-minute-walk distance (6MWD) MCID (95% confidence interval) estimates from the validation (Pulmonary Hypertension Association Registry) data on the basis of a change in physical component score of five. *Age and baseline 6MWD are analyzed as continuous variables. For definition of abbreviations, see Figure 3.