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The Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins School of Medicine, Baltimore, MDDepartment of Epidemiology, Johns Hopkins University, Baltimore, MD
The Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins School of Medicine, Baltimore, MDDivision of Cardiology, Johns Hopkins School of Medicine, Baltimore, MDDepartment of Epidemiology, Johns Hopkins University, Baltimore, MD
To investigate the association between using febuxostat and cardiovascular events.
Methods
Systematic search of randomized controlled trials was performed using PubMed/MEDLINE, Cochrane review, and EMBASE databases through April 17, 2019. Meta-analysis was performed using random effect model and estimates were reported as risk difference (RD) with 95% CIs. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. The main outcomes of interest were cardiovascular mortality and all-cause mortality.
Results
A total of 15 randomized controlled trials (16,070 participants) were included. The mean ± SD age was 58.1±11.7 years. At the median follow-up of 6.4 months, use of febuxostat was not associated with statistically significant risk of cardiovascular mortality (RD, 0.12%; 95% CI, -0.25% to 0.49%; I2=48%; low certainty evidence), all-cause mortality (RD, 0.20%; 95% CI, -0.28% to 0.68%; I2 =60%; very low certainty evidence), major adverse cardiovascular events (RD, 0.40%; 95% CI, -0.34% to 1.13%; I2=26%; low certainty evidence), myocardial infarction (RD, -0.06%; 95% CI, -0.29% to 0.17%; I2 =0%; moderate certainty evidence), stroke (RD, 0.10%; 95% CI, -0.15% to 0.35%; I2=0%; moderate certainty evidence), or new-onset hypertension (RD, 1.58%; 95% CI, -0.63% to 3.78%; I2=58%; very low certainty evidence). These findings were consistent in patients with existing cardiovascular disease.
Conclusion
This meta-analysis suggested that use of febuxostat was not associated with higher risk of mortality or adverse cardiovascular outcomes in patients with gout and hyperuricemia. The results were limited by low to moderate certainty of evidence.
A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy.
Traditionally, this has been achieved either by reducing the production of uric acid with the use of xanthine oxidase inhibitors and/or enhancement of uric acid excretion with a uricosuric agent.
Recent studies have raised safety concerns regarding the use of febuxostat in the management of hyperuricemia. The Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) trial reported a higher risk of cardiovascular mortality with the use febuxostat vs control
However, since the mortality hazard was shown in a single randomized controlled trial (RCT), assessment of the drug’s safety profile in larger population settings is warranted. A recent meta-analysis
has found that febuxostat did not increase the risk of major adverse cardiovascular events (MACE) but may increase the risk of cardiovascular death. Herein, we conducted a systematic review and meta-analysis by including a higher number of RCTs than the previously published meta-analysis to examine the effects of febuxostat on mortality and MACE in patients with gout.
Methods
This trial level meta-analysis was conducted in accordance with Cochrane collaboration guidelines
The protocol of the present study was registered at PROSPERO register (CRD42019133121).
Study Search and Selection Criteria
The literature search was performed using electronic databases of PubMed/MEDLINE, Cochrane review, and EMBASE without language limitations through April 17, 2019, by two independent reviewers (H.E. and S.U.). The following keywords were used: febuxostat, hyperuricemia, gout, and clinical trial (Supplementary Material, available online at http://www.mcpiqojournal.org). References of retrieved studies were screened for further relevant studies suitable for this meta-analysis.
The pre-determined inclusion criteria were: (1) RCTs comparing febuxostat vs control (placebo or allopurinol) among adult patients with hyperuricemia; and (2) studies reporting mortality and cardiovascular endpoints of interest. There were no restrictions on language, sample size, and follow-up durations. We excluded reviews, editorials, letters, and non-human studies. We also excluded observational studies as they carry risk of selection and attrition bias to minimize the risk of confounding.
Data Extraction and Quality Assessment
The data abstraction was performed on a pre-specified data collection form by two independent reviewers (A.B. and A.J.), and any discrepancy was resolved by a third reviewer (A.A.). The following information was abstracted: baseline characteristics of trials and participants, crude point estimates, raw events, sample sizes, and follow-up duration. Two reviewers (A.J. and A.B.) assessed the quality and certainty of the evidence under the supervision of third reviewer (A.A.) using the Jadad scale
The main outcomes of interest were cardiovascular mortality and all-cause mortality. The additional endpoints were MACE, myocardial infarction (MI), stroke, and new-onset hypertension. The definition of MACE in each of the involved trials is shown in Supplemental Table 3.
Statistical Analysis
Outcomes were pooled using a random effects Mantel-Haenszel model. The DerSimonian and Laird method was used for estimation of τ2. We reported effect sizes as risk difference (RD) with 95% CI. The 95% CIs that did not cross zero were considered statistically significant. We reported the number needed to treat or harm (NNT/H) for all outcomes. We used the I2 statistic to measure statistical heterogeneity; I2>50% was considered to have significant heterogeneity. Sensitivity analyses were performed by limiting the results to patients with pre-existing cardiovascular disease (CVD), and by excluding one trial at a time. To assess whether the current meta-analysis was powered to assess 30% difference between groups with moderate heterogeneity, power analysis was performed as suggested by Borenstein et al.
Analyses were performed using Review Manager (RevMan) Version 5.3 (Copenhagen, Denmark: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014).
Results
Of 661 articles, 67 full-text articles were reviewed after removal of duplicates. Finally, 15 RCTs encompassing 16,070 participants met the inclusion criteria (Figure 1).
Role of febuxostat in retarding progression of diabetic kidney disease with asymptomatic hyperuricemia: a 6-months open-label, randomized controlled trial.
Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial.
Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout.
Efficacy and safety of febuxostat extended release and immediate release in patients with gout and moderate renal impairment: phase II placebo-controlled study.
An allopurinol-controlled, multicenter, randomized, double-blind, parallel between-group, comparative study of febuxostat in Chinese patients with gout and hyperuricemia.
Tables 1 and 2 report baseline characteristics of trials and participants. The mean ± SD age was 58.1±11.7 years. The proportion of patients with hypertension varied from 27.7% to 100.0% and diabetes 6.9% to 100.0%. The median follow-up across the trials was 6.4 months (range: 4 to 24 months).
Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout.
Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial.
Efficacy and safety of febuxostat extended release and immediate release in patients with gout and moderate renal impairment: phase II placebo-controlled study.
Role of febuxostat in retarding progression of diabetic kidney disease with asymptomatic hyperuricemia: a 6-months open-label, randomized controlled trial.
Febuxostat 10–40 mg vs non-febuxostat group (allopurinol 100 mg given if serum uric acid was elevated)
November 2013–October 2014
Japan
36
Elderly patients aged ≥65 y with hyperuricemia (serum uric acid >7.0 to ≤9.0 mg/dL) who had one or more risks for cerebral, cardiovascular, or renal disease
Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout.
Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial.
An allopurinol-controlled, multicenter, randomized, double-blind, parallel between-group, comparative study of febuxostat in Chinese patients with gout and hyperuricemia.
The use of febuxostat was not associated with a significant risk of cardiovascular mortality (RD, 0.12%; 95% CI, -0.25% to 0.49%; P=.53; I2=48%; NNH=454.5; low certainty evidence) (Figure 2A) or all-cause mortality (RD, 0.20%; 95% CI, -0.28% to 0.68; P=.42; I2 =60%; NNH=149.3; very low certainty of evidence) (Figure 2B).
Figure 2(A) Forest plot of cardiovascular mortality. (B) Forest plot of all-cause mortality. M = Mantel; H = Haenszel.
The use of febuxostat was not associated with a significant risk of MI (RD, -0.06%; 95% CI, -0.29% to 0.17%; P=.61; I2 =0%; NNH=128.2; moderate certainty evidence), MACE (RD, 0.40%; 95% CI, -0.34% to 1.13%; P=.29 I2 =26%; NNH=155.3; low certainty evidence), stroke (RD, 0.10%; 95% CI, -0.15% to 0.35%; P=.43; I2 =0%; NNH=476.2; moderate certainty evidence), or new onset hypertension (RD, 1.58%; 95% CI, -0.63% to 3.78%; P=.16; I2 =58%; NNH=44.8; very low certainty evidence) compared with control (Supplemental Figures 4A to 4D, available online at http://www.mcpiqojournal.org).
Sensitivity Analyses
In sensitivity analyses restricted to trials including only patients with pre-existing CVD (4 RCTs, 7442 participants), use of febuxostat was not associated with significant risk of cardiovascular mortality (RD, 0.48%; 95% CI, -0.58% to 1.54%; P=.37; I2 =30%; NNH=117.8; low certainty evidence), all-cause mortality (RD, 0.32%; 95% CI, -1.30% to 1.94%; P=.70; I2 =46%; NNH=94.8; low certainty evidence), MACE (RD 0.24% [-1.01% to 1.49%]; P=.71; I2 =0%; NNH=377.4; moderate certainty evidence), and MI (RD, -0.30%; 95% CI, -1.03% to 0.43%; P=.42; I2 =0%; NNH=396.8; moderate certainty evidence) (Supplemental Figures 5A to D, available online at http://www.mcpiqojournal.org). Sensitivity analysis by excluding one trial at a time was not associated with significant changes in the results (Supplemental Table 4, available online at http://www.mcpiqojournal.org).
Discussion
In this systematic review and meta-analysis of 15 RCTs including more than 16,000 patients, we found that febuxostat was not associated with a significant risk of cardiovascular or all-cause mortality among patients with gout and hyperuricemia compared with control. In conformity, there was no significant risk of MACE, nonfatal MI, stroke, or new-onset hypertension with use of febuxostat vs control.
Observational studies have suggested a beneficial cardiovascular outcome with febuxostat in patients with gout.
Major cardiovascular events in patients with gout and associated cardiovascular disease or heart failure and chronic kidney disease initiating a xanthine oxidase inhibitor.
found a significant increased risk of adverse cardiovascular events and mortality with febuxostat and the association was dose dependent. In 2018, White et al
published the CARES trial, which was the largest reported RCT that evaluated the cardiovascular safety of febuxostat in patients with gout compared with allopurinol. This trial, which included 6190 patients, found no overall difference in MACE between the two groups, but there were more cardiovascular and all-cause mortality events in the febuxostat group. However, we did not find an association of febuxostat with cardiovascular or all-cause mortality in our analysis of pooled RCT data that included more than 16,000 patients. The CARES trial included patients with higher cardiovascular risk who had events rate more than 10% higher than the other trials, which could have contributed to this higher mortality rates seen in this trial.
had included 10 trials and found that febuxostat did not increase the risk of MACE but may increase the risk of cardiovascular death. We found that MACE was defined differently across different RCTs (Supplemental Table 5, available online at http://www.mcpiqojournal.org) and using it as a primary outcome is unreliable. Therefore, we focused on cardiovascular mortality as the primary outcome. Our study has many other important strengths, including extensive search focusing on cardiovascular events, examining multiple individual MACE endpoints, a larger number of included trials, performance of a key sensitivity analysis, and analyzing the data using the RD instead of risk ratio because we are handling a dataset in which many of the event frequencies were zero; thus, using the risk ratio may exaggerate the effect of treatment.
On the other hand, our study also has some limitations worth mentioning. First, although we included a higher number of trials than the prior meta-analysis,
there was high heterogeneity of study populations across the various trials. We tried to overcome that by pooling results using the random effects model and doing sensitivity analysis. Second, among these trials, the number of cardiovascular events were low in both febuxostat and control arms of the trials and this is likely because the primary endpoints of most of these studies were not cardiovascular events. Third, there were only limited number of studies which included only patients with history of CVD.
If future studies are planned, we recommend further trials that measure cardiovascular events and mortality as an outcome, defining MACE, and comparing the outcomes among different doses of febuxostat over a longer follow-up duration. Finally, there are many ongoing trials that are measuring cardiovascular events and mortality as an outcome such as the Febuxostat versus Allopurinol Streamlined Trial (FAST)
Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large prospective, randomised, open, blinded endpoint study comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia.
trial (ISRCTN72443728) and other trials with specific types of patients; for example, the Lowering-hyperuricemia Treatment on Cardiovascular Outcomes in Peritoneal Dialysis Patients (LUMINA) trial (NCT03200210) includes only patients on peritoneal dialysis, and the The Impact of Urate-lowering Therapy on Kidney Function (IMPULsKF) trial (NCT03336203) includes patients with chronic kidney disease. All of these trials will help in estimating the associated risk of cardiovascular events and mortality with using febuxostat.
Conclusion
This meta-analysis including 16,070 participants showed that there was no significant difference in cardiovascular mortality, all-cause mortality, MACE, MI, stroke, and new-onset hypertension between febuxostat and the control group.
Acknowledgments
The protocol was registered at the PROSPERO register (CRD42019133121). The authors Dr Kabir A. Yousuf for his assistance with administrative support.
A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy.
Role of febuxostat in retarding progression of diabetic kidney disease with asymptomatic hyperuricemia: a 6-months open-label, randomized controlled trial.
Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial.
Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout.
Efficacy and safety of febuxostat extended release and immediate release in patients with gout and moderate renal impairment: phase II placebo-controlled study.
An allopurinol-controlled, multicenter, randomized, double-blind, parallel between-group, comparative study of febuxostat in Chinese patients with gout and hyperuricemia.
Major cardiovascular events in patients with gout and associated cardiovascular disease or heart failure and chronic kidney disease initiating a xanthine oxidase inhibitor.
Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large prospective, randomised, open, blinded endpoint study comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia.
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