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.

2. Disclosure
•Honoraria, Ajanta Pharmaceuticals

3. Defining the ASSOCIATION
HYPERURICEMIA
GOUT
•Cardiovascular Disease
• Coronary Artery Disease
• Vascular Events
• Peripheral Arterial Disease
•Hypertension
•Chronic Kidney Disease
Causality
Epiphenomenon

4. 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.

5. 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

6. 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

7. 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

8. 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

9. 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.

10. 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.

11. 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.

12. 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

13. 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)

14. 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.

15. 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.

16. 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

17. 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.

18. 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.

19. 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