INTRODUCTION AND AIMS: Premature cardiovascular death is the leading cause of death amongst ESRD patients. Increased left ventricular mass (LVM) is strongly associated with all cause and cardiovascular mortality. Reduction of LVM may reduce cardiovascular morbidity and mortality. Allopurinol has been shown to reduce LVM in randomised controlled trials in chronic kidney disease, diabetes and ischaemic heart disease. We investigated whether allopurinol might regress left ventricular mass indexed to body surface area (LVMI) in a haemodialysis population by conducting a multicentre double blind randomised controlled trial.
METHODS: 107 patients consented to participate in this study. Following screening and a dose finding study in 11 patients, 80 haemodialysis patients were randomly assigned to allopurinol 300mg or placebo after each dialysis session for 1 year. LVMI was assessed by cardiac magnetic resonance imaging performed on the post HD day at baseline and after a year of treatment. Images were analysed offline by an observer blinded to treatment allocation. A t test was used to determine between groups differences in change in LVMI.
RESULTS: Participants on placebo and allopurinol were well matched, pre-HD diastolic BP was lower in the allopurinol group (table 1).
Patient Characteristics
| All Participants | Placebo | Allopurinol | p Value | |
|---|---|---|---|---|
| Number | 79 | 40 | 39 | |
| Age (years) | 58 ± 12 | 58 ± 13 | 58 ± 12 | 0.90 |
| Male (%) | 60.8 | 57.7 | 64.1 | 0.55 |
| Baseline Mean Ultrafiltration volumes (l) | 1.8 ± 0.9 | 1.8 ± 0.8 | 1.8 ± 0.8 | 0.98 |
| Uric Acid (micromol/L) | 367 ± 88 | 365 ± 88 | 365 ± 86 | 0.99 |
| Baseline Pre-HD Systolic BP (mmHg) | 141 ± 23 | 144 ± 25 | 139 ± 21 | 0.31 |
| Baseline Pre-HD Diastolic BP (mmHg) | 72 ± 13 | 75 ± 13 | 69 ± 12 | 0.04 |
| All Participants | Placebo | Allopurinol | p Value | |
|---|---|---|---|---|
| Number | 79 | 40 | 39 | |
| Age (years) | 58 ± 12 | 58 ± 13 | 58 ± 12 | 0.90 |
| Male (%) | 60.8 | 57.7 | 64.1 | 0.55 |
| Baseline Mean Ultrafiltration volumes (l) | 1.8 ± 0.9 | 1.8 ± 0.8 | 1.8 ± 0.8 | 0.98 |
| Uric Acid (micromol/L) | 367 ± 88 | 365 ± 88 | 365 ± 86 | 0.99 |
| Baseline Pre-HD Systolic BP (mmHg) | 141 ± 23 | 144 ± 25 | 139 ± 21 | 0.31 |
| Baseline Pre-HD Diastolic BP (mmHg) | 72 ± 13 | 75 ± 13 | 69 ± 12 | 0.04 |
Patient Characteristics
| All Participants | Placebo | Allopurinol | p Value | |
|---|---|---|---|---|
| Number | 79 | 40 | 39 | |
| Age (years) | 58 ± 12 | 58 ± 13 | 58 ± 12 | 0.90 |
| Male (%) | 60.8 | 57.7 | 64.1 | 0.55 |
| Baseline Mean Ultrafiltration volumes (l) | 1.8 ± 0.9 | 1.8 ± 0.8 | 1.8 ± 0.8 | 0.98 |
| Uric Acid (micromol/L) | 367 ± 88 | 365 ± 88 | 365 ± 86 | 0.99 |
| Baseline Pre-HD Systolic BP (mmHg) | 141 ± 23 | 144 ± 25 | 139 ± 21 | 0.31 |
| Baseline Pre-HD Diastolic BP (mmHg) | 72 ± 13 | 75 ± 13 | 69 ± 12 | 0.04 |
| All Participants | Placebo | Allopurinol | p Value | |
|---|---|---|---|---|
| Number | 79 | 40 | 39 | |
| Age (years) | 58 ± 12 | 58 ± 13 | 58 ± 12 | 0.90 |
| Male (%) | 60.8 | 57.7 | 64.1 | 0.55 |
| Baseline Mean Ultrafiltration volumes (l) | 1.8 ± 0.9 | 1.8 ± 0.8 | 1.8 ± 0.8 | 0.98 |
| Uric Acid (micromol/L) | 367 ± 88 | 365 ± 88 | 365 ± 86 | 0.99 |
| Baseline Pre-HD Systolic BP (mmHg) | 141 ± 23 | 144 ± 25 | 139 ± 21 | 0.31 |
| Baseline Pre-HD Diastolic BP (mmHg) | 72 ± 13 | 75 ± 13 | 69 ± 12 | 0.04 |
53 patients completed the study and were included in the final analysis, by intention to treat, one participant (on allopurinol) was excluded from analysis prior to unblinding because of a protocol breach. A reduction in urate was achieved with allopurinol: change in urate (μmol/L) placebo +21 ± 100, allopurinol -44 ± 84, p=0.01. In an unadjusted analysis allopurinol did not regress LVMI - change in LVMI (g/m2): placebo +3.6 ± 10.4, allopurinol +1.6 ± 11 p=0.49. In a sub-group analysis of those patients who achieved a reduction in urate of 20% or more with allopurinol, allopurinol significantly reduced LVMI- change in LVMI placebo +3.6 ± 10.4 versus -2.9 ± 7 p= 0.03 (figure 1).
CONCLUSIONS: Compared with placebo, treatment with allopurinol 300mg did not regress LVMI in haemodialysis patients over a year of therapy. However, in those patients on allopurinol who achieved a 20% reduction in urate there was a significant reduction in LVMI suggesting effect of allopurinol on LVMI is dependent on effective dose. A larger scale trial to determine if allopurinol reduces CV outcomes in HD patients is warranted, with a strategy to randomise those who can attain a 20% reduction in urate with allopurinol in a run-in phase.
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