Early indicators of disease progression in Fabry disease that may indicate the need for disease-specific treatment initiation: findings from the opinion-based PREDICT-FD modified Delphi consensus initiative

Abstract

Objectives: The PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease (PREDICT-FD) initiative aimed to reach consensus among a panel of global experts on early indicators of disease progression that may justify FD-specific treatment initiation.

Design and setting: Anonymous feedback from panellists via online questionnaires was analysed using a modified Delphi consensus technique. Questionnaires and data were managed by an independent administrator directed by two non-voting cochairs. First, possible early indicators of renal, cardiac and central/peripheral nervous system (CNS/PNS) damage, and other disease and patient-reported indicators assessable in routine clinical practice were compiled by the cochairs and administrator from panellists' free-text responses. Second, the panel scored indicators for importance (5-point scale: 1=not important; 5=extremely important); indicators scoring ≥3 among >75% of panellists were then rated for agreement (5-point scale: 1=strongly disagree; 5=strongly agree). Indicators awarded an agreement score ≥4 by >67% of panellists achieved consensus. Finally, any panel-proposed refinements to consensus indicator definitions were adopted if >75% of panellists agreed.

Results: A panel of 21 expert clinicians from 15 countries provided information from which 83 possible current indicators of damage (kidney, 15; cardiac, 15; CNS/PNS, 13; other, 16; patient reported, 24) were compiled. Of 45 indicators meeting the importance criteria, consensus was reached for 29 and consolidated as 27 indicators (kidney, 6; cardiac, 10; CNS/PNS, 2; other, 6; patient reported, 3) including: (kidney) elevated albumin:creatinine ratio, histological damage, microalbuminuria; (cardiac) markers of early systolic/diastolic dysfunction, elevated serum cardiac troponin; (CNS/PNS) neuropathic pain, gastrointestinal symptoms suggestive of gastrointestinal neuropathy; (other) pain in extremities/neuropathy, angiokeratoma; (patient-reported) febrile crises, progression of symptoms/signs. Panellists revised and approved proposed chronologies of when the consensus indicators manifest. The panel response rate was >95% at all stages.

Conclusions: PREDICT-FD captured global opinion regarding current clinical indicators that could prompt FD-specific treatment initiation earlier than is currently practised.

Keywords: cardiomyopathy; chronic renal failure; genetics; stroke medicine.

Figure 1

PREDICT-FD modified Delphi consensus methodology. ^aA threshold median likelihood score of 7.5 was set a priori. For questions about the likelihood of initiating treatment, agreement for initiation was sought in round 2 if a scenario was awarded a median score of ≥7.5 and agreement not to initiate treatment sought if the score was <7.5. Similarly, for questions about cessation of treatment, agreement to stop treatment was sought in round 2 if a scenario was awarded a median score ≥7.5 and agreement not to stop treatment sought if the score was <7.5. PREDICT-FD, PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease.

Figure 2

Chronology of consensus indicators. (A) *Indicator tested for, but not achieving, consensus in round 3. (B) †Indicators in red text achieved consensus both as currently used, and suitable for future adoption, because they are not available in all centres. Two further indicators (abnormal PET/MRI and increased serum lyso Gb3) that were included in round 2 of the initiative but were not taken forward to round 3 are not shown here based on guidance from the cochairs. (C) *Indicator tested for, but not achieving, consensus in round 3. Other indicators tested for, but not achieving, consensus, and which are not included here owing to their lack of specificity were: biomarkers; patient-reported outcomes; absenteeism owing to ill health; and palpitations. ^aIndicators that currently would be likely to trigger FD-specific treatment initiation. ^bIn isolation, probably insufficient justification for FD-specific treatment initiation. ^cMicroalbuminuria could be a trigger for further investigation, such as confirmatory biopsy, and subsequent initiation of disease-specific treatment. ^dIncluding decreased myocardial strain and strain rate, tissue Doppler abnormalities, enlarged left atrium, abnormal wall motion or pulmonary vein abnormalities. ^eIncluding shortened PR interval, non-SVT and symptomatic bradycardia. ACR, albumin:creatinine ratio; AF, atrial fibrillation; FD, Fabry disease; GFR, glomerular filtration rate; LGE, late gadolinium enhancement; LVH, left ventricular hypertrophy; lyso Gb3, globotriaosylsphingosine; NT-pro-BNP, N-terminal probrain natriuretic peptide; PET, positron emission tomography; SVT, sustained VT; VT, ventricular tachycardia.