Cardiovascular Risks of Probenecid Versus Allopurinol in Older Patients With Gout

Kim, Seo Young; Neogi, Tuhina; Kang, Eun Ha; Li, Jun; Desai, Rishi; Zhang, Mary Ann; Solomon, Daniel H.

doi:10.1016/j.jacc.2017.12.052

Cited by 73 publications

(43 citation statements)

References 37 publications

(47 reference statements)

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“…However, the lack of placebo limits our ability to determine whether the mortality results of the CARES study are due to beneficial effects of allopurinol or deleterious effects of febuxostat. With respect to uricosuric ULT, a large observational study using Medicare data compared CV risk for allopurinol and probenecid (7). Those with gout who initiated probenecid had lower risk of hospitalization for MI or stroke compared with allopurinol initiators (HR 0.80, 95% CI 0.69–0.93), with consistent results regardless of baseline CKD or CV status (7).…”

Section: What Uncertainties Arise From the Results Of Cares ?mentioning

confidence: 99%

“…With respect to uricosuric ULT, a large observational study using Medicare data compared CV risk for allopurinol and probenecid (7). Those with gout who initiated treatment with probenecid had a lower risk of hospitalization for MI or stroke compared with allopurinol initiators (HR 0.80 [95% CI 0.69-0.93]), with consistent results regardless of baseline chronic kidney disease or CV status (7). However, without performance of a prospective RCT with similar design features to the CARES trial, including assessment of serum urate lowering and gout flares, the Medicare study results cannot be compared to the results of the CARES trial.…”

Section: Strengths Of the Studymentioning

confidence: 99%

“…The XOI febuxostat is commonly used in ULT when allopurinol is not tolerated, or when the maximum allopurinol dose chosen has not achieved lowering of the urate level to the selected target. Since risk factors and manifestations of CV disease are particularly common in gout (7), questions raised by the CARES trial findings are fundamentally important to clinical practice. From our perspective as rheumatologist gout researchers, we recap the original purpose of the CARES trial, evaluate the study results, and cite and discuss other relevant recent and ongoing trials.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

New Perspectives in Rheumatology: Implications of the Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities Trial and the Associated Food and Drug Administration Public Safety Alert

Choi

Neogi

Stamp

et al. 2018

Arthritis & Rheumatology

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Recently, the US Food and Drug Administration (FDA) issued a public safety alert, responding to the results of the now-published Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities (CARES) trial. The CARES trial showed no significant difference between allopurinol and febuxostat in the primary composite end point of cardiovascular (CV) events in subjects with gout and established CV comorbidities at baseline. However, there was a significantly increased risk of CV and all-cause mortality with febuxostat. Urate-lowering therapy (ULT) is central to the long-term management of gout, and xanthine oxidoreductase inhibitor (XOI) therapy is the consensus first-line approach. Allopurinol is generally the first XOI used, but febuxostat is an effective XOI option, and is commonly used when allopurinol is not tolerated. These data are further relevant since CV comorbidities are common in gout. Here, we examine why the CARES trial was done, and discuss other, ongoing comparative studies of febuxostat and allopurinol whose results are awaited. We assess the strengths and limitations of the CARES trial, and appraise the robustness and biologic plausibility of the results. The CARES trial does not prove that febuxostat raises CV mortality risk, but suggests greater risk with febuxostat than allopurinol. The CARES trial results do not support first-line use of febuxostat ULT, and raise questions about febuxostat placement at various pharmacologic ULT decision tree branches. Alternatives to febuxostat that are frequently effective include allopurinol dose escalation and uricosuric therapy alone or combined with allopurinol. The FDA safety alert highlights the need for shared ULT medical decision-making with gout patients, including discussion of the CV safety of febuxostat.

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Section: What Uncertainties Arise From the Results Of Cares ?mentioning

confidence: 99%

Section: Strengths Of the Studymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

New Perspectives in Rheumatology: Implications of the Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities Trial and the Associated Food and Drug Administration Public Safety Alert

Choi

Neogi

Stamp

et al. 2018

Arthritis & Rheumatology

Self Cite

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“…This suggests that the anti-oxidant effects of allopurinol are unlikely to fully explain the improved CV prognosis with this agent, supporting the possibility that reduced uric acid itself contributes to improved CV prognosis. [87][88][89] Several mechanisms could account for the epidemiological link between hyperuricaemia and CV risk. Although circulating uric acid has potentially beneficial antioxidant properties, intracellular uric acid stimulates nicotinamide adenine dinucleotide phosphate (NADPH) oxidases which generate reactive oxygen species (ROS).…”

Section: Major Adverse Cardiovascular Eventsmentioning

confidence: 99%

“…In a propensity score-matched cohort study there was an 11% reduction in a composite outcome of MI, stroke and CV death and a 32% reduction in all-cause mortality among 7127 patients receiving allopurinol 85. This suggests that the anti-oxidant effects of allopurinol are unlikely to fully explain the improved CV prognosis with this agent, supporting the possibility that reduced uric acid itself contributes to improved CV prognosis [87][88][89]. Prospective studies with febuxostat and probenecid have also reduced adverse CV events, together with reduced uric acid concentrations in patients with gout.…”

mentioning

confidence: 99%

Uric acid and the cardio‐renal effects of SGLT2 inhibitors

Bailey

2019

Diabetes Obesity Metabolism

141

118

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Sodium/glucose co-transporter-2 (SGLT2) inhibitors, which lower blood glucose by increasing renal glucose elimination, have been shown to reduce the risk of adverse cardiovascular (CV) and renal events in type 2 diabetes. This has been ascribed, in part, to haemodynamic changes, body weight reduction and several possible effects on myocardial, endothelial and tubulo-glomerular functions, as well as to reduced glucotoxicity. This review evaluates evidence that an effect of SGLT2 inhibitors to lower uric acid may also contribute to reduced cardiorenal risk.Chronically elevated circulating uric acid concentrations are associated with increased risk of hypertension, CV disease and chronic kidney disease (CKD). The extent to which uric acid contributes to these conditions, either as a cause or an aggravating factor, remains unclear, but interventions that reduce urate production or increase urate excretion in hyperuricaemic patients have consistently improved cardio-renal prognoses. Uric acid concentrations are often elevated in type 2 diabetes, contributing to the "metabolic syndrome" of CV risk. Treating type 2 diabetes with an SGLT2 inhibitor increases uric acid excretion, reduces circulating uric acid and improves parameters of CV and renal function. This raises the possibility that the lowering of uric acid by SGLT2 inhibition may assist in reducing adverse CV events and slowing progression of CKD in type 2 diabetes. SGLT2 inhibition might also be useful in the treatment of gout and gouty arthritis, especially when co-existent with diabetes. K E Y W O R D Scardiac, gout, obesity, renal, sodium/glucose co-transporter-2 (SGLT2) inhibitor, type 2 diabetes, uric acid | CARDIO-RENAL EFFECTS OF SGLTINHIBITORSSeveral recent large prospective randomized studies in type 2 diabetes have observed reduced CV risk and improved renal function during treatment with an SGLT2 inhibitor. 3 In the EMPA-REG OUTCOME trial, treatment with empagliflozin was associated with a reduced composite 3-point MACE of CV death, nonfatal myocardial infarction (MI) and stroke by 14%; CV mortality was reduced by 38%, overall mortality by 32% and hospitalization for heart failure by 35%. 4 Empagliflozin also reduced by 39% the deterioration in nephropathy, measured as a composite of progression to macroalbuminuria, doubling of

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Hyperuricemia treatment in acute heart failure patients does not improve their long‐term prognosis: A propensity score matched analysis from the AHEAD registry

Pavlušová

Jarkovský

Benešová

et al. 2019

Clinical Cardiology

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Background Hyperuricemia is associated with a poorer prognosis in heart failure (HF) patients. Benefits of hyperuricemia treatment with allopurinol have not yet been confirmed in clinical practice. The aim of our work was to assess the benefit of allopurinol treatment in a large cohort of HF patients. Methods The prospective acute heart failure registry (AHEAD) was used to select 3160 hospitalized patients with a known level of uric acid (UA) who were discharged in a stable condition. Hyperuricemia was defined as UA ≥500 μmoL/L and/or allopurinol treatment at admission. The patients were classified into three groups: without hyperuricemia, with treated hyperuricemia, and with untreated hyperuricemia at discharge. Two‐ and five‐year all‐cause mortality were defined as endpoints. Patients without hyperuricemia, unlike those with hyperuricemia, had a higher left ventricular ejection fraction, a better renal function, and higher hemoglobin levels, had less frequently diabetes mellitus and atrial fibrillation, and showed better tolerance to treatment with angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers and/or beta‐blockers. Results In a primary analysis, the patients without hyperuricemia had the highest survival rate. After using the propensity score to set up comparable groups, the patients without hyperuricemia had a similar 5‐year survival rate as those with untreated hyperuricemia (42.0% vs 39.7%, P = 0.362) whereas those with treated hyperuricemia had a poorer prognosis (32.4% survival rate, P = 0.006 vs non‐hyperuricemia group and P = 0.073 vs untreated group). Conclusion Hyperuricemia was associated with an unfavorable cardiovascular risk profile in HF patients. Treatment with low doses of allopurinol did not improve the prognosis of HF patients.

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Cardiovascular Risks of Probenecid Versus Allopurinol in Older Patients With Gout

Abstract: In this large cohort of 38,888 elderly gout patients, treatment with probenecid appears to be associated with a modestly decreased risk of CV events including MI, stroke, and HF exacerbation compared with allopurinol.

Cited by 73 publications

References 37 publications

New Perspectives in Rheumatology: Implications of the Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities Trial and the Associated Food and Drug Administration Public Safety Alert

New Perspectives in Rheumatology: Implications of the Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities Trial and the Associated Food and Drug Administration Public Safety Alert

Uric acid and the cardio‐renal effects of SGLT2 inhibitors

Hyperuricemia treatment in acute heart failure patients does not improve their long‐term prognosis: A propensity score matched analysis from the AHEAD registry

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