The role of urate-lowering treatment on cardiovascular and renal disease: evidence from CARES, FAST, ALL-HEART, and FEATHER studies

Abstract

Hyperuricemia has long been known to cause gout, and has recently been correlated with cardiovascular disease, hypertension, and renal disease. In the last few years, several large clinical studies have confirmed that hyperuricemia is a significant and independent risk factor for hypertension, ischemic heart disease, and heart failure, after an extensive adjustment for almost all the possible confounding conditions. This article reviews published literature on the subject, and describes ongoing studies on the use of urate-lowering therapy for cardiovascular and renal diseases.

Keywords:

• Uric acid
• cardiovascular diseases
• renal disease

Introduction

Alteration of serum uric acid (SUA) level has been linked to several diseases. Hyperuricemia has long been known to cause gout, and recently has been correlated with cardiovascular disease, hypertension, and renal disease. In addition, recent studies have demonstrated that hyperuricemia may contribute to the development or progression of these diseases^1–3. Besides gout, some evidence suggests that urate-lowering treatments may be effective to prevent and/or treat hyperuricemia-related cardiovascular and renal disease⁴.

The association of uric acid with cardiovascular and renal disease

Hyperuricemia has long been established as the major etiologic factor in gout. When SUA levels go beyond its saturation point, monosodium urate crystallizes and deposits into peripheral joints and surrounding tissues, causing gouty arthritis⁵.

The association of hyperuricemia with cardiovascular disease was described 2 centuries ago¹, and more recently many observational studies showed that SUA levels correlate with cardiovascular diseases, including ischemic heart disease, heart failure, hypertension, and stroke⁶. For a long time, however, the observed association between SUA elevations and cardiovascular disease was considered “epiphenomenal” and not causal. Whether SUA has a causal relationship with cardiovascular and renal diseases is still debated, although compelling evidence is growing⁷. In the last few years, several large clinical studies have confirmed that hyperuricemia is a significant and independent risk factor for hypertension, ischemic heart disease, and heart failure, after an extensive adjustment for almost all of the possible confounding conditions^2,8,9. It was reported that the overall risk of cardiovascular disease mortality increased by 15% for each increase of 1 mg/dl of uric acid⁴. Hyperuricemia has also been considered a causal factor for renal disease, metabolic syndrome, insulin resistance, type 2 diabetes, and non-alcoholic fatty liver disease, with a linear dose–response relationship^10–13.

Hyperuricemia was found to be a risk factor for the onset of chronic kidney disease (CKD) in a cohort¹⁴, and to be significantly associated with the progression of CKD¹⁵. Two open-label small-size single-center clinical studies suggested that allopurinol prevented renal function reduction in patients with CKD^16,17.

The post-hoc analysis of a clinical study on the long-term (5-year) oral administration of febuxostat in 116 patients with hyperuricemic gout showed that maintenance of improved eGFR was correlated with a reduction in SUA from baseline¹⁸. Therefore, it is important to evaluate the long-term effect of SUA reduction on renal function in hyperuricemic patients with impaired renal function.

Pathophysiological mechanisms activated by hyperuricemia have been extensively investigated, and some links with cardiovascular and renal diseases have been described. The pivotal enzyme of uric acid metabolism, xanthine oxidoreductase (XOR), induces production of reactive oxygen species (ROS) and promotes oxidative stress. At vascular level, ROS production is linked with inflammation, and reduced nitric oxide (NO) production, resulting in endothelial dysfunction. Reduced vasodilation leads to renal detrimental effects⁴.

Effect of urate-lowering therapy on all-cause and cardiovascular mortality in hyperuricemic patients without gout

Xanthine oxidase inhibitor drugs have several beneficial effects that may improve outcomes in cardiovascular disease. Besides lowering SUA, they improve endothelial function in patients with heart failure, type 2 diabetes, and smokers, reduce left ventricular mass in patients with ischemic heart disease, reduce left ventricular hypertrophy in patients with type 2 diabetes mellitus and chronic kidney disease, lower blood pressure, and decrease arterial stiffness and carotid intima-media thickness progression^19–21.

Whether urate-lowering therapy is beneficial for hyperuricemic patients without gout is still undetermined, because of the co-existence of different risk factors (advanced age, chronic kidney disease, cardiovascular disease, obesity, metabolic syndrome, and alcohol or smoking habits).

The survival benefit of allopurinol for all-cause death was reported in an observational study of hyperuricemic veterans in the US²², and a cohort study showed that allopurinol initiation reduces the risk of all-cause mortality by 19% in hyperuricemic patients²³. A randomized controlled trial showed that allopurinol reduces systolic and diastolic blood pressure in adolescents with early-onset hypertension and hyperuricemia²⁴.

Hyperuricemic patients who received urate-lowering therapy had potentially better survival than patients who did not, in a retrospective case-matched cohort study that enrolled 40,118 Taiwanese individuals aged ≥17 years who had never used urate-lowering therapy (ULT) and who had never had gout, during a mean follow-up of 6.4 years²⁵. The mortality rate was compared in 3,088 hyperuricemic patients who did not receive ULT vs reference subjects (no hyperuricemia, no gout, no ULT) matched for age and sex (hyperuricemic patients/reference subjects), and in 1,024 hyperuricemic patients who received ULT vs 1,024 hyperuricemic patients who did not receive ULT (matched 1:1 based on their propensity score and the index date of ULT prescription). After adjustment, hyperuricemic patients who did not receive ULT had increased risks of all cause (hazard ratio = 1.24; 95% confidence interval = 0.97–1.59) and CVD (2.13; 1.34–3.39) mortality relative to the matched reference subjects. Hyperuricemic patients treated with ULT had a lower risk of all-cause death (0.60; 0.41–0.88) relative to hyperuricemic patients who did not receive ULT²⁵.

Based on pre-clinical data and of observational studies, some clinical trials are being carried out with the aim of addressing the questions whether urate-lowering therapy is effective to improve cardiovascular outcomes and prevent progression of chronic kidney disease in patients without a history of gout.

Ongoing clinical studies on the cardiovascular protective effect of urate lowering therapy

Cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular comorbidities (CARES) study

Although the general safety and tolerability findings of febuxostat and allopurinol in patients with gout have been acceptable for clinical use, their long-term CV safety has not been well known. The CARES trial represents the first randomized, controlled clinical trial that will evaluate the long-term safety of xanthine oxidase inhibitors in gout patients with a history of prior CV events or disease, attempting to rule out a post-approval level of risk after ∼3–5 years of treatment in the study population.

This trial is a phase 3B, multi-center, prospective, double blind, randomized trial in which febuxostat is being compared with allopurinol on CV outcomes in ∼7,500 patients with gout and well-defined CV disease. The primary objective of the trial is to compare the risk of a 4-component major adverse CV event (4-component MACE) (CV death, non-fatal MI, non-fatal stroke, and unstable angina with urgent revascularization) during treatment with febuxostat and allopurinol. Patients are randomized in a 1:1 ratio to receive either febuxostat or allopurinol once daily. Randomization will be stratified based on baseline renal function. Patients randomized to febuxostat will initially receive the 40-mg dose once daily and will remain on this dose if the serum uric acid is <6.0 mg/dL after 2 weeks of therapy. If the serum uric acid is >6.0 mg/dL at the week 2 visit, their dose of febuxostat will be 80 mg once daily for the remainder of the trial.

The CARES is establishing CV safety of the xanthine oxidase inhibitor febuxostat in patients with gout and increased CV risk. The study has been ongoing since 2010, and has randomized approximately one-third of the study population. The results of the CV safety of febuxostat in patients with elevated CV risk could allow for calculation of the risk vs benefit for the more common lower CV risk groups with gout and hyperuricemia²⁶.

Febuxostat vs allopurinol streamlined trial (FAST) study

When completed, the Febuxostat vs Allopurinol Streamlined Trial (FAST) will help to establish the cardiovascular safety of febuxostat and allopurinol in a population with high cardiovascular risk. Efficacy end-points will also help to define the role of febuxostat in the management of patients with gout²⁷. FAST is a prospective, randomized, open-label, blinded end-point evaluation (PROBE) design trial started to compare the cardiovascular safety of febuxostat and allopurinol, according to real-world use.

Patients aged at least 60 years who are taking chronic allopurinol are recruited through general practice lists, and randomized to either allopurinol or febuxostat and followed-up for a minimum of 3 years. Allopurinol dose is determined during the allopurinol lead-in phase and febuxostat is started at 80 mg daily and increased to 120 mg daily if SUA is above the European League Against Rheumatism (EULAR) target at 2 weeks. Figure 1 shows a study overview.

Figure 1. Overview of the FAST study. Reproduced with permission²⁷.

The primary end-point is the first occurrence of any event included in the Anti-Platelet Trialists’ Collaboration (APTC) composite end-point (hospitalization for non-fatal myocardial infarction/biomarker positive acute coronary syndrome: non-fatal stroke; or death due to a cardiovascular event)²⁷.

The following secondary end-points will be evaluated: hospitalization for non-fatal myocardial infarction/biomarker positive acute coronary syndrome; non-fatal stroke; cardiovascular death; all cause mortality; and hospitalization for heart failure, for unstable, new or worsening angina, for coronary or cerebral revascularization, for transient ischemic attack, for non-fatal cardiac arrest, for venous and peripheral arterial vascular thrombotic event, and for arrhythmia with no evidence of ischemia²⁷.

An exploratory efficacy end-point is also pre-specified: the proportion of patients whose urate level is ≥6.0; < 6.0; and <5.0 mg/dL after 1, 2, and 3 years of treatment²⁷.

Allopurinol and cardiovascular outcomes in patients with ischemic heart disease (ALL-HEART study)

The ALL-HEART study is a clinical trial that aims to address whether allopurinol added to usual therapy improves cardiovascular outcomes in patients with ischemic heart disease (IHD)¹⁹. In addition, data will be collected on any improvements in quality-of-life, and an analysis of the health economics of the use of allopurinol in the UK National Health Service (NHS) in patients with IHD will be performed¹⁹.

The study is a multi-center, controlled, prospective, randomized, open-label, blinded end-point (PROBE) superiority trial of allopurinol (up to 600 mg daily) vs no treatment added to usual therapy in patients aged at least 60 years with IHD. The study will end when the required number of primary end-points have occurred. In total, 5,215 patients with ischemic heart disease from primary care will be randomized to allopurinol or no additional treatment (Figure 2)¹⁹.

Figure 2. ALL-HEART study overview. In total, 5,215 patients aged over 60 years with ischemic heart disease will be randomized to receive allopurinol or no additional therapy, in addition to their usual care, then followed up for an expected average of 4 years for outcomes. Reproduced with permission¹⁹.

Patients are randomized to either allopurinol or no drug, to be given in addition to the usual medications. Allopurinol is started at 100 mg/day and titrated up to 600 mg/day in patients with eGFR ≥60 mL/min at screening visit, or up to 300/day in patients with eGFR 30–59 mL/min at screening visit. Allopurinol is then continued at the maximum or maximum tolerated dose for up to 5 years¹⁹.

Six weeks after starting allopurinol, blood samples are taken for full blood count, urea and electrolytes, creatinine, eGFR, and urate. Adverse events, concomitant medications, compliance with allopurinol, and dose of allopurinol are recorded. Data on adverse events, gout flares, and compliance with therapy are collected by questionnaire at annual intervals throughout the study. Patients complete the EuroQol five dimensions questionnaire (EQ-5D) and Seattle Angina Questionnaire quality-of-life questionnaires after 1 year and at the end of the trial¹⁹.

The primary outcome is the composite cardiovascular end-point of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The secondary outcomes are non-fatal myocardial infarction; non-fatal stroke; cardiovascular death; all-cause mortality; all cardiovascular hospitalizations; hospitalization for acute coronary syndrome; coronary revascularization; hospitalization for acute coronary syndrome or coronary revascularization; hospitalization for heart failure; quality-of-life (EQ-5D and Seattle Angina Questionnaire); and cost-effectiveness of allopurinol¹⁹.

Ongoing clinical studies on the renal protective effects of urate lowering drugs

The FEbuxostat vs placebo rAndomized controlled Trial regarding reduced renal function in patients with Hyperuricemia complicated by chRonic kidney disease stage 3 (FEATHER) study is the first to prospectively assess the long-term (2-year) effect of SUA reduction on renal function in hyperuricemic patients with concurrent renal impairment²⁸.

This randomized placebo controlled study is based on the presumed inverse correlation between eGFR and SUA concentration. It was designed to examine whether febuxostat prevents a further reduction in renal function, as assessed with eGFR in patients with hyperuricemia, who have never had gout and are complicated by CKD stage 3²⁸. The FEATHER study should investigate not only the renoprotective efficacy of the urate lowering drug febuxostat, but also give some clues regarding how low the uric acid level should be lowered to achieve the objectives.

The FEATHER study is a prospective, multi-center, double blind, randomized, placebo-controlled clinical study (Figure 3). Between November 2012–December 2013, 400 patients with hyperuricemia who have never had gout and are complicated by CKD stage 3a or 3b, who are aged 20 years or older, and without gouty arthritis were recruited. Patients were randomly assigned to either the febuxostat (starting with 10 mg/day and titrating up to 40 mg/day) or the control group. Patients in the study groups receive the allocated study drug for 108 weeks. The primary end-point of the FEATHER study is eGFR slope (change in eGFR per year, mL/min/1.73 m²/year) during the 108-week study period. The secondary end-points are: (1) the amount (mL/min/1.73 m²) and rate (%) of change in eGFR from baseline to weeks 24, 48, 72, and 108; (2) the amount (mg/dL) and the rate (%) of change in SUA concentration from baseline to week 108; (3) the proportion of patients whose SUA concentration became ≤6.0 mg/dL; (4) the incidence of renal deterioration defined by the commencement of dialysis or doubled serum creatinine concentration; (5) changes in biomarkers for renal function (serum cystatin C), oxidative stress (urinary 8-hydroxydeoxyguanosine and urinary L-type fatty acid-binding protein), and inflammation (serum C-reactive protein), as well as in variables for cardiovascular events (12-lead electrocardiogram, serum N-terminal Pro Brain Natriuretic Peptide (NT-Pro BNP), and albumin urine/creatinine ratio) to monitor the outcomes of ULT from baseline to week 108; (6) incidence of gouty arthritis; and (7) incidence of adverse events²⁸.

Figure 3. Flow diagram of the FEATHER study. Reproduced with permission²⁸.

Conclusions

The central cause of gout is well known, and effective treatments are available. In addition, a relationship has been demonstrated between uric acid level and cardiovascular risk on one side and renal function on the other. The pathophysiological mechanisms responsible for the association suggest that the use of a urate lowering therapy in the long-term may reduce cardiovascular risk, and the progression of chronic kidney disease. Large randomized clinical trial results are expected to demonstrate the efficacy and safety of such an approach.

Transparency

Declaration of funding

This editorial was funded by Fondazione Menarini.

Declaration of financial/other relationships

RP declares speakers bureau from Teijin Pharma and Algorytm SAS. RP also declares consultancy/advisory fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, and sigma-tau. Peer reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no other relevant financial relationships to disclose.

Acknowledgments

Editorial assistance for this supplement was provided by Content Ed Net funded by Fondazione Menarini. The author thanks Thomas Macdonald for his speech at the Symposium “Uric Acid and cardiovascular disease: back to pathophysiology” held in Bologna, December 1–3, 2016, on which this article was based in part.