Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout

White, William Β.; Saag, Kenneth G.; Becker, Michael A.; Borer, Jeffrey S.; Gorelick, Philip B.; Whelton, Andrew; Hunt, Barbara; Castillo, Majin; Gunawardhana, Lhanoo

doi:10.1056/nejmoa1710895

Cited by 685 publications

(589 citation statements)

References 20 publications

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“…Considerable observational data suggest that allopurinol is associated with cardiovascular benefit 10, 19, 20. Yet, febuxostat, a more potent xanthine oxidase inhibitor and hypouricemic agent, has recently been shown in a randomized clinical trial to lead to increased cardiovascular and all‐cause mortality compared with allopurinol 21. The ongoing ALL‐HEART (Allopurinol and Cardiovascular Outcomes in Patients With Ischemic Heart Disease) randomized trial will assess whether patients with ischemic heart disease derive cardiovascular benefit from allopurinol therapy versus standard of care 22…”

Section: Discussionmentioning

confidence: 99%

Association of Gout With Long‐Term Cardiovascular Outcomes Among Patients With Obstructive Coronary Artery Disease

Pagidipati

Clare

Keenan

et al. 2018

JAHA

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BackgroundEpidemiological studies demonstrating a relationship between gout and cardiovascular disease are older and predate modern cardiovascular preventive therapy. We assessed the contemporary association between gout and cardiovascular disease in patients with obstructive coronary artery disease.Methods and ResultsData were from the Duke Databank for Cardiovascular Diseases, which followed up patients undergoing cardiac catheterization with obstructive coronary artery disease at Duke University Medical Center (1998–2013). We assessed the relationship between gout diagnosis at baseline or during follow‐up and the primary composite outcome of cardiovascular death, myocardial infarction, or stroke, adjusting for differences in baseline clinical factors. Secondary end points included cardiovascular death and all‐cause mortality. New, postbaseline, gout diagnosis was included as a time‐dependent covariate. Among 17 201 patients, 1406 (8.2%) had baseline gout and a high burden of cardiovascular risk factors, but high rates of optimal medical therapy. Over a median follow‐up of 6.4 years, gout diagnosis at time of catheterization was not associated with the primary outcome (hazard ratio [95% confidence interval], 1.05 [0.96–1.15]; P=0.31) or cardiovascular death (hazard ratio [95% confidence interval], 1.10 [0.99–1.22]; P=0.08), but was associated with increased all‐cause mortality (hazard ratio [95% confidence interval], 1.13 [1.05–1.23]; P=0.002). After including new, postbaseline, gout diagnosis, the instantaneous risk of the primary outcome was significantly associated with prior gout diagnosis (hazard ratio [95% confidence interval], 1.15 [1.07–1.25]; P=0.0004).ConclusionsA clinical history of gout is associated with worse outcomes in a contemporary population of patients with obstructive coronary artery disease. This increased risk exists despite high levels of optimal baseline cardiovascular disease medical therapy, suggesting that residual cardiovascular risk is not addressed by standard medical therapy.

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Section: Discussionmentioning

confidence: 99%

Association of Gout With Long‐Term Cardiovascular Outcomes Among Patients With Obstructive Coronary Artery Disease

Pagidipati

Clare

Keenan

et al. 2018

JAHA

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“…The preclinical studies of febuxostat have shown no cardiovascular toxic effects. A large number of patients discontinued participation in the trial, and in the intention-to-treat analysis includes merely 10% of patients (White et al, 2018). It is therefore recommended that, within the clinical setting, related risk factors should be monitored for increasing the safety of the drug treatment.…”

Section: Safetymentioning

confidence: 99%

Febuxostat in patients with hyperuricemia and severe chronic kidney disease

Yang¹

2018

Afr. J. Pharm. Pharmacol.

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Febuxostat is a non-purine, selective inhibitor of both isoforms of xanthine oxido-reductase (XOR).Its pharmacokinetics is not dependent on renal clearance, and it may be advantageous in patients with chronic kidney disease (CKD). Although febuxostat is effective in patients with mild-to-moderate CKD, its efficacy and safety in patients with severe CKD remain unclear. This retrospective study included patients with an estimated glomerular filtration rate (eGFR) of < 30 ml/min/1.73 m 2 and hyperuricemia, who received febuxostat. The study was performed at Kaohsiung Medical University Hospital between January, 2015 and December, 2015. Changes were observed in the serum uric acid level, rate of achieving the target uric acid level (<6.0 mg/dL), changes in the eGFR, treatment dosage, and adverse events. 217 patients (65.9 ± 15.1 yrs, 145 males and 72 females) with severe CKD and hyperuricemia were included. Febuxostat significantly lowered the serum uric acid level (9.4 ± 1.9 at baseline and 5.6 ± 1.9 ml/min after treatment, P < 0.001). The serum uric acid level was <6 mg/dl in 126 patients (58.1%). There were no significant changes in eGFR (17.6 ± 7.4 at baseline and 17.8 ± 8.9 ml/min after treatment, P = 0.642) or indices of liver dysfunction. Adverse events were found in 5 patients, all adverse events improved after discontinuing febuxostat. This study demonstrated that febuxostat is efficacious and well tolerated in severe CKD patients with hyperuricemia, although renal function monitoring may be needed.

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“…Febuxostat is indicated for the chronic management of hyperuricemia in patients with gout, and the most common adverse events in patients taking febuxostat are liver function abnormalities, nausea, arthralgia and rash [24]. Recently, in patients with gout and coexisting cardiovascular disease, patients treated with febuxostat were found to have an increased risk of cardiovascular death compared with those treated with allopurinol [25].Although monotherapy use of XOIs can be efficacious, there are challenges associated with the utilization of XOIs and with patients achieving sUA target. These challenges include inadequate dosing, lack of follow-up monitoring and dose adjustment, as well as poor drug adherence [26].…”

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confidence: 99%

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Budget impact of adding lesinurad for second-line treatment of gout: a US health plan perspective

et al. 2018

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Aim: Estimate budget impact of adopting lesinurad as add-on to allopurinol for urate-lowering therapy in gout. Methods: A budget impact model was developed for a US payer perspective, using a Markov model to estimate costs, survival and discontinuation in a one-million-member health plan. The population included patients failing first-line gout therapy, followed for 5 years. Results: Incremental costs of adding lesinurad versus no lesinurad were US$241,907 and US$1,098,220 in first and fifth years, respectively. Cumulative 5-year incremental cost was US$3,633,440. Estimated incremental mean cost per treated patient with gout per year was US$112. The mean per-member per-month cost increased by US$0.06. Conclusion: Initiating lesinurad would result in an incremental per-member per-month cost of US$0.06 over 5 years. Gout is the most common type of inflammatory arthritis in adults, affecting approximately eight million people in the USA [1]. Gout occurs when serum uric acid (sUA) supersaturates in the serum and begins to precipitate as monosodium urate crystal deposits in the joints, tendons and other soft tissues [2][3][4][5]. Hyperuricemia, defined as an sUA level above 6.8 mg/dl, can be asymptomatic, but the shedding of urate crystals into the joint space may cause joint inflammation and severe pain known as gout flares or gouty arthritis [6]. Severe cases of gout may result in the development of tophi, which are deposits of monosodium urate crystals [7]. Moreover, hyperuricemia is associated with cardiovascular [8][9][10][11] and renal morbidity [12] and an increased risk of mortality [13,14].In 2010, gout was responsible for 2.3% of 38.6 million hospitalizations and approximately five million ambulatory care visits [15]. Patients with gout incur greater direct and indirect costs compared with those without gout [16]. The total all-cause cost of care for US patients with gout is estimated to be US$11,663 per person or US$31.8 billion overall, while the cost of gout-attributable expenses is estimated to be US$2805 per person or US$7.7 billion overall [17]. Another published analysis found the incremental annual cost of care for a gout patient to exceed US$3000 compared with nongouty individuals [18]. Available data show that the costs (total, medical and pharmacy costs) of care associated with uncontrolled gout are substantial and increase with disease severity (defined as higher sUA levels, greater frequency of flares or tophaceous gout) [16,19]. Gout is also associated with poor health-related quality of life, even adjusting for comorbidities [20].The current standard of care for gout includes patient education on diet, lifestyle, treatment objectives, medication adherence and management of comorbidities. Xanthine oxidase inhibitor (XOI) therapy with allopurinol or febuxostat is indicated as the first-line pharmacologic urate-lowering therapy (ULT) to aid patients in achieving an sUA target of <6 mg/dl [21]. Allopurinol, a purine analog, has been the dominant ULT in the USA since 1966 and febuxostat is a nonpu...

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Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout

Cited by 685 publications

References 20 publications

Association of Gout With Long‐Term Cardiovascular Outcomes Among Patients With Obstructive Coronary Artery Disease

Association of Gout With Long‐Term Cardiovascular Outcomes Among Patients With Obstructive Coronary Artery Disease

Febuxostat in patients with hyperuricemia and severe chronic kidney disease

Budget impact of adding lesinurad for second-line treatment of gout: a US health plan perspective

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