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Treating Asymptomatic Hyperuricemia for Better CV Outcomes

To Treat or Not to Treat.

This is a frequent question we encounter in practice. Here's looking into the latest studies on whether treating patients with Asymptomatic Hyperuricemia with urate lowering therapy helps improves cardiovascular outcomes.

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Treating Asymptomatic Hyperuricemia for Better CV Outcomes

  1. 1. Disclosure •Honoraria, Ajanta Pharmaceuticals
  2. 2. Defining the ASSOCIATION HYPERURICEMIA GOUT •Cardiovascular Disease • Coronary Artery Disease • Vascular Events • Peripheral Arterial Disease •Hypertension •Chronic Kidney Disease Causality Epiphenomenon
  3. 3. Disease Associations with GOUT •Coronary Heart Disease •Vascular Events •Peripheral Arterial Disease •Increased CV-related Deaths •Higher in Women •Higher in Young Patients Andres M, Sivera F, Quintanilla FA, et al. Int J Clin Rheumatol 2015; 10 (5): 329-34.
  4. 4. Disease Associations with HYPEURICEMIA •Incident Coronary Artery Disease •Heart Failure •CV Mortality (Women) •All Cause Mortality (Men) •Higher in Women Vasalle C, Mazzone A, Sabtino L, Carpegianni C. Diseases 2016; 4:12
  5. 5. Factors Behind Increased CV Risks in Gout Traditional Risk Factors •Hypertension •Dyslipidemia (Oxidized LDL) •Insulin Resistance / Diabetes •Obesity •Physical Inactivity •Cigarette Smoking Non-Traditional Risk Factors •Low Grade Systemic Inflammation •Xanthine Oxidase (XO) Activity •HYPERURICEMIA
  6. 6. Serum Uric Acid and CV Disease Modified from Lanaspa MA, Sanchez-Lozada LG, Choi YJ, et al. J Biol Chem 2012; 287: 40732-40744 XO Overactivity / XO “Overfeeding” (Genetics, Induced) (Food, Fructose, Purines) Increased OXIDATIVE STRESS Increased URIC ACID LEVELS Increased Cellular Entry of Uric Acid Increased INTRACELLULAR URIC ACID Increased Intracellular Oxidative Stress (Reduced endothelial nitric oxide, mitochondrial dysfunction) CV Disease Hypertension Chronic Kidney Disease
  7. 7. The Duality of Serum Uric Acid Anti-Oxidant • Increased in response to oxidative stress • Endothelial Protection • Direct correlation with total anti-oxidant capacity; inverse correlation with oxidative stress Pro-Oxidant • Increases Oxidative Stress • Increases inflammation and cytokines (via innate response) • Induces monocyte apoptosis Vasalle C, Mazzone A, Sabtino L, Carpegianni C. Diseases 2016; 4:12
  8. 8. The Switch? For Uric Acid There is a 15% increase in cardiovascular mortality for every 1 mg/dl increase in uric acid levels. (Reference: SUA 5.5 mg/dl) Borghi C, Desideri G. Hypertension 2016; 67: 496-8.
  9. 9. Typologies of Hyperuricemia Cardiovascular – Hypeuricemia • Cardiovascular Disease • Hypertension • Chronic Kidney Disease Xanthine Oxidase induced free radical production during uric acid formation Gout – Hypeuricemia • Gout • Tophi • Nephrolithiases Uric Acid deposition and its consequences CRYSTAL Uric Acid SOLUBLE Uric Acid Borghi C, Desideri G. Hypertension 2016; 67: 496-8.
  10. 10. Proposed Staging System for Gout Asymptomatic Hyperuricemia Acute Gout Interval Gout Chronic Gout STAGE A At high risk for gout but no evidence of crystal deposition STAGE B Evidence of Crystal Deposition but without symptoms or signs of gout STAGE C Evidence of Crystal Deposition and with prior or current episodes of gout flares STAGE D Advanced gout requiring specialized interventions Dalbeth N, Stamp L. Ann Rheum Dis 2014; 73: 1598-1600.
  11. 11. Concerns with Stage B Gout Patients with asymptomatic hyperuricemia with silent MSU deposits suffered from more severe coronary atherosclerosis. Andres M, Quintanilla MA, Sivera F, et al. Arthritis Rheumatol 2016; 68: 1531-9
  12. 12. Allopurinol & CV Outcomes in Patients with HPN MacIsaac RL, Salatski J, Higgins P, et al. Hypertension 2016; 67: 535-540. 4064 Propensity Score Matched Patients with HPN, Age >65 years from the UK CPRD EXCLUDED: Renal Insufficiency, COPD, BA, Rheumatoid Arthritis, Migraine High Dose Allopurinol (>300 mg) Low Dose Allopurinol (<300 mg) Allopurinol Naïve STROKE CV EVENTS (MI/ ACS)
  13. 13. Allopurinol & CV Outcomes in Patients with HPN HAZARD RATIOS CV EVENTS STROKE Allopurinol Treated vs. Allopurinol Naïve 0.63 (95% CI 0.44, 0.89) 0.50(95% CI 0.32, 0.80) High Dose Allopurinol vs. Allopurinol Naïve 0.38(95% CI 0.21, 0.67) 0.29(95% CI 0.13, 0.62) Low Dose Allopurinol vs. Allopurinol Naïve 0.89(95% CI 0.58, 1.38) 0.66(95% CI 0.37, 1.18) High Dose Allopurinol vs. Low Dose Allopurinol 0.65(95% CI 0.46, 0.93) 0.58(95% CI 0.36, 0.94) MacIsaac RL, Salatski J, Higgins P, et al. Hypertension 2016; 67: 535-540.
  14. 14. Allopurinol & CV Outcomes in Patients with HPN •Allopurinol may have BP- and Uric Acid- INDEPENDENT effects on •Vasculature George J, Carr E, Davies J, et al. Circulation 2006; 114: 2508-16. •Regression on LV hypertrophy Kao MP, Ang DS, Gandy SJ, et al. J Am Soc Nephrol 2011; 22: 1382-9. •Improved endothelial function Beattie CJ, Fulton RL, Higgins P, et al. Hypertension 2014; 64: 1102-7. •Despite similar reductions in serum uric acid, no comparable benefit observed in Probenecid treated patients (vs. Allopurinol) Farquharson CA, Butler R, Hill A, et al. Circulation 2002; 106: 221-6.
  15. 15. XOIs for Preventing CV Events 81RCTs in adult patients treated with XOIs for >28days INDEPENDENT of condition being treated or CV risk profile of patients (10,684 patients, 6,434 patient years) SOURCES: PubMed, EMBASE, Web of Science, Cochrane and Lilacs Purine XOI (Allopurinol/ Oxypurinol) Non Purine XOI (Febuxostat/ Topiroxostat) Placebo • Major adverse CV Events • New or Worsening HPN • New or Worsening HF • Deaths • Total CV Events • Serious CV Events • Serious AEs Bredemeier M, Lopes LM, Eisenreich MA, et al. BMC Cardiovascular Disorders 2018; 18:24
  16. 16. XOIs in Preventing CV Events Outcomes Purine XOI Non Purine XOI Major Adverse CV Events 0.65(95% CI 0.41, 1.05) 65s 1.13(95% CI 0.40, 3.19) 19s Death 0.94(95% CI 0.62, 1.44) 74s 0.71(95% CI 0.15, 3.40) 19s MI or Urgent Revascularization 0.38(95% CI 0.17, 0.83) 62s 2.76 (95% CI 0.62, 12.35) 19s Stroke 0.73(95% CI 0.16, 3.29) 60s 0.54(95% CI 0.07, 4.07) 19s CV Death 0.86(95% CI 0.50, 1.46) 66s 0.45(95% CI 0.06, 3.48) 19s New or Worsening HPN 0.32(95% CI 0.18, 0.58) 55s 0.70(95% CI 0.43, 1.12) 19s New or Worsening HF 0.90(95% CI 0.66, 1.24) 59s 1.79(95% CI 0.43, 7.49) 18s Bredemeier M, Lopes LM, Eisenreich MA, et al. BMC Cardiovascular Disorders 2018; 18:24.
  17. 17. XOIs in Preventing CV Events Outcomes Purine XOI Non Purine XOI Total CV Events 0.57(95% CI 0.46, 0.72) 65s 0.90(95% CI 0.62, 1.30) 19s Serious CV Events 0.59(95% CI 0.46, 0.76) 65s 1.04 (95% CI 0.58, 1.87) 19s Serious Adverse Events 0.88(95% CI 0.70, 1.10) 64s 1.12 (95% CI 0.75, 1.66) 19s Major Adverse CV Events (Excluding trials in patients without CV Risk Factors) 0.61(95% CI 0.38, 0.98) 47s Benefit for Primary Prevention Major Adverse CV Events (Trials in patients with prior coronary events) 0.42 (95% CI 0.23, 0.76) 9s Benefit for Secondary Prevention Bredemeier M, Lopes LM, Eisenreich MA, et al. BMC Cardiovascular Disorders 2018; 18:24.
  18. 18. SUMMARY • Hyperuricemia and CV Disease arise from Xanthine Oxidase hyperactivity • Hyperuricemia is both a risk marker and a risk factor for CV Disease • Patients with Stage B Gout are at risk for severe coronary atherosclerosis • There are Allopurinol - intervention studies showing reduction in coronary events, incident HPN and serious CV events • Further studies are needed to demonstrate benefits in CV prevention with ULTs

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