MANAGEMENT OF GOUT IN CKD AND CVD - A BRIEF DESCRIPTION

gout management in CKD & CVD

1. Management of Gout in CKD & CVD Dr Ritasman Baisya MD, DM , MRCP (UK) Assistant Professor, Rheumatology AIIMS , Kaly ani

2. I have no actual or potential conflict of interest in relation to this presentation Disclosure

3. Points of discussion Gout in CKD - Drugs for flare & prophylaxis Urate-lowering therapy (ULT) Therapy in RRT Unmet needs Gout with CVD - Drugs for flare & prophylaxis Battle between ULTs Research agenda Take-home points

4. Gout – inflammatory arthritis Acute onset of a monoarthritis- fist MTP ( podagra ) Later stage – chronic inflammatory arthritis with tophi 0.1% to 10% - Prevalence of gout in population Stamp, L. K., Farquhar, H., Pisaniello , et al . (2021). Management of gout in chronic kidney disease: A G-CAN Consensus Statement on the research priorities. Nature Reviews Rheumatology, 17(10), 633-641.

5. G out & CKD cross-talk Gout in CKD – 24% cases with GFR < 60, while 2.9% cases with GFR > 90 ml/min/1.73 m2 ( impaired UA removal ) CKD in gout - 70% cases GFR < 60, 20% cases GFR < 25 ml/min/1.73 m2 ( urate nephropathy ) Reduced GFR – early tophi in gout Renal medullary echogenicity in severe gout Polyarticular flare – common in CKD Old female, diuretic use – risk factors in CKD

6. Management of gout Treatment of acute gouty flare Prophylaxis to prevent flare Lower SUA (Urate-lowering therapy ) Optimise dietary and lifestyle factors as appropriate. Kannuthurai, V., & Gaffo , A. (2023). Management of Patients with Gout and Kidney Disease: A Review of Available Therapies and Common Missteps. Kidney360, 4(9), e1332.

7. Reasons for poor outcome in Gout & CKD Variability of outcome measures Failure to report result stratified by renal function Exclusion of CKD in gout trial Reduced efficacy of ULT & adverse effects of kidney Conflicting management guidelines Adverse effects of drugs Lack of evidence Clinical concerns Stamp LK, Farquhar H, Pisaniello HL et al . Management of gout in chronic kidney disease: a G-CAN Consensus Statement on the research priorities. Nat Rev Rheumatol . 2021 Oct;17(10):633-641

8. Kannuthurai V, Gaffo A. Management of Patients with Gout and Kidney Disease: A Review of Available Therapies and Common Missteps. Kidney360. 2023 Sep 1;4(9):e1332-e1340 Drugs for gout flare & prophylaxis in CKD

9. P- Male & postmenopausal female with > 2 gout flare in last 1 year ( N- 184) I - self-administered low-dose colchicine (1.8 mg total over 1 hour) and high-dose colchicine (4.8 mg total over 6 hours) with placebo. O- proportion of responder in high dose versus placebo ( primary ) , low dose versus placebo ( secondary ) Definition of Responders - pretreatment pain score within 12 hours of flare onset and a 50% reduction in pain within 24 hours of the first dose of study medication without the use of rescue medication during that time frame AGREE STUDY Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW. High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the first multicenter , randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum. 2010 Apr;62(4):1060-8.

10. Conclusion - Low dose group was effective in reducing flare within 24 hours Decreased intake of rescue medicine was seen in low dose group Adverse effect profile is less in low dose group Responders- % improvement in pain score ( AGREE study )

11. ULT in CKD

12. Author Study design Exposure Result Whelton et al, 2011 FOCUS study: open label extension study – 116 out , Cr cl > 50-79 Febuxostat 40, 80 or 120 mg/day The effects of SUA reduction were associated with maintenance or improvement in eGFR over a 5-year follow-up period Pai et al, 2013 Cohort study, 183 GFR <90 Allopurinol 100 mg /d eGFR remained stable in patients treated with allopurinol Control group presented a significant decline in kidney function Shibagaki et al, 2014 Cohort 70 , GFR < 45 , UA > 8 Febuxostat CKD stage 3 shows increased GFR , stage 4 , 5 showed decline in GFR Goicoechea et al. 2010 & Goicoechea et al. 2015 Open randomised 113 GFR < 60 Allopurinol 100 mg/day (n=57) vs. and continuation of usual therapy (n=56) After 2 years, the allopurinol arm had significantly reduced SUA 47% lower risk of kidney disease progression compared with the control group Kanji et al. 2015 SRM from 5 RCT Allopurinol vs placebo vs conservative No significant conclusion Comparison of different studies

13. P - Ninety-six gout patients with moderate-to-severe renal impairment were enrolled in a 12-month multicenter, randomised, double-blind, placebo-controlled study . I- 30 mg BD , 40/80 mg OD C- Placebo O- Change in serum Cr level / estimated GFR from baseline Saag KG, Whelton A, Becker MA, MacDonald P, Hunt B, Gunawardhana L. Impact of Febuxostat on Renal Function in Gout Patients With Moderate-to-Severe Renal Impairment. Arthritis Rheumatol . 2016 Aug;68(8):2035-43 Saag et al

14. Figure 1 - No significant reduction of Cr /GFR from baseline at 12 month in both Febuxostat group compared to placebo Figure 2 - SUA < 6 mg/ dL in febuxostat group is significantly more compared to placebo RESULT

15. Kannuthurai V, Gaffo A. Management of Patients with Gout and Kidney Disease: A Review of Available Therapies and Common Missteps. Kidney360. 2023 Sep 1;4(9):e1332-e1340 ULT recommendation in Gout - CKD

16. Management of gout flare in RRT (stage 5 CKD ) Flare & prophylaxis Guideline Colchicine Flare - 0.6 mg as a single dose; FDA-approved label states that treatment course should not be repeated more frequently than every 14 days Prophylaxis – Avoid NSAID Restricted use Steroid May be used IL1 inhibitor A nakinra - <2.5% of the administered dose of anakinra is removed by HD /PD ; consider dose reduction , 100 mg every other day Canakinumab - no dose reduction is needed, though clinical experience is limited Vargas-Santos, A. B., & Neogi , T. (2017). Management of Gout and Hyperuricemia in CKD. American Journal of Kidney Diseases : The Official Journal of the National Kidney Foundation, 70(3), 422.

17. ULT in RRT Guideline Allopurinol I ntermittent HD: start with 100 mg alternate days post-dialysis Daily HD: additional 50% of dose may be required post-dialysis; Daily PD: start with 50 mg/day; All types of RRT: up-titrate dose with 50 mg-increments every 2–5 weeks, measure serum urate pre-dialysis. Febuxostat Despite some successful reports of dialysis patients using febuxostat up to 80 mg/day, this agent is not FDA-approved for use in dialysis due to a lack of trials in this population Uricosuric Contraindicated Pegloticase No dose adjustment Management with ULT in RRT Vargas-Santos, A. B., & Neogi , T. (2017). Management of Gout and Hyperuricemia in CKD. American Journal of Kidney Diseases : The Official Journal of the National Kidney Foundation, 70(3), 422.

18. Mis -steps

19. R esearch priorities for people with gout & CKD The Gout, Hyperuricemia, and Crystal-Associated Disease Network (G-CAN) proposed priorities

20. R esearch priorities for Pharmacotherapy in gout & CKD

21. Management of gout in CVD

22. Gout – CVD crosstalk Comorbid CVD and/or HF and gout are frequently encountered in clinical practice O besity , HTN , metabolic syndrome, dyslipidemia – shared risk factors C hronic inflammation, oxidative stress – shared pathogenesis A combined approach of lifestyle changes, diet modification, and pharmacotherapy Certain medications have cardiovascular benefits relevant to patients with gout and CVD- losartan , SGLT2 inhibitor , CCB , low dose aspirin

23. Acute gout & prophylaxis Drug Recom Comment Colchicine – flare & prophylaxis First line for flare & Prophylaxis Potentially decreased MI NSAID Last line for flare Level of risk potentially differs according to agent, All agents increase the risk of HF Low dose naproxen Steroid Short term – second line for flare Limited data for acute gout. Potentially safe for short durations in CVD and HF IL1 inhibitor No data No evidence to suggest increased CV or HF events Canakinumab may reduce CV events Mouradjian MT, Plazak ME, et al Pharmacologic Management of Gout in Patients with Cardiovascular Disease and Heart Failure. Am J Cardiovasc Drugs. 2020 Oct;20(5):431-445. doi : 10.1007/s40256-020-00400-6. PMID: 32090301.

24. ULT in CVD ALLOPURINOL FEBUXOSTAT

25. CARES trial , 2018  M ulticenter , double-blind, non-inferiority trial involving patients with gout and CVD P- 6190 patients I- Febuxostat or allopurinol (followed for a median of 32 months) O- A composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization

26. Result

27. The trial had an excessive drop-out rate (56.6%) Most events occurred during the drug-free stage Imbalanced use of NSAIDs or low-dose aspirin The absence of a non-treated group  Limitations of CARES trial

28. P – Subjects with SUA>8 (n = 2,269) , US centres I – Febuxostat (F) 40 mg or 80 mg, or allopurinol (A) 300 mg /200 mg O -proportion of subjects in each treatment group with sUA <6.0 mg/ dL at the final visit R- F ( 40 mg ) was statistically non-inferior to A , but F (80 mg) was superior to both (P < 0.001). R- Adjudicated (APTC) CV event rates - 0.0% for F (40 mg) and 0.4% for both F 80 mg and A . Becker, M.A.; Schumacher, H.R .;et al . The Urate-Lowering Efficacy and Safety of Febuxostat in the Treatment of the Hyperuricemia of Gout: The CONFIRMS Trial.  Arthritis Res. Ther .   2010 ,

29. FAST trial , 2020 Mackenzie IS, Ford I, Nuki G, Hallas J, Hawkey CJ, et al FAST Study Group. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. Lancet. 2020 Nov 28;396(10264):1745-1757 Study design - Prospective , randomised, open-label, blinded-endpoint, non-inferiority in the UK, Denmark, and Sweden P- Gout , 60 years or older, already receiving allopurinol, had at least one additional CV risk factor. I - After a lead-in phase in which the allopurinol dose was optimised, patients were randomly assigned ( 1:1) to continue allopurinol (at the optimised dose) or start febuxostat at 80 - 120 mg/day O - The primary outcome was a composite of hospitalisation for non-fatal myocardial infarction or biomarker-positive acute coronary syndrome; non-fatal stroke; or cardiovascular death.

30. Result Febuxostat was non-inferior to allopurinol for the primary composite endpoint F ewer deaths in febuxostat group (62 CV deaths vs 82 CV deaths) T reatment with febuxostat was not associated with an increase in cardiovascular death with a baseline history of CV events

31. Research agenda- gout with CVD

32. Take home points CKD is common in gout & vice versa Colchicine dose adjustment is needed in CKD , better to avoid in RRT NSAID restriction is important in CKD & CVD ( low dose naproxen ) Short-duration steroid can be used in flare with CKD Allopurinol ( < 100mg /d) is first-line ULT in CKD Febuxostat ( 40-80 mg /day ) in mild -moderate CKD , avoid in HD Target SUA< 6 mg/dl is more important than GFR adjustment Uricosurics are contraindicated in CKD Colchicine can be used in flare & prophylaxis with CVD Both allopurinol and febuxostat ( FAST , CONFIRMS) are safe in CVD There is a research gap in RCT , outcome measures & guideline in gout – CKD

33. Thank you