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Effects of Febuxostat on Mortality and Cardiovascular Outcomes

A Systematic Review and Meta-Analysis of Randomized Controlled Trials

      Abstract

      Objective

      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.

      Abbreviations and Acronyms:

      CARES trial (The Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities), CVD (cardiovascular disease), MACE (major adverse cardiovascular events), MI (myocardial infarction), RCT (randomized controlled trials), RD (risk difference)
      Gout is a chronic inflammatory condition characterized by the deposition of monosodium urate crystals within the organs.
      • Chhana A.
      • Lee G.
      • Dalbeth N.
      Factors influencing the crystallization of monosodium urate: a systematic literature review.
      ,
      • Ragab G.
      • Elshahaly M.
      • Bardin T.
      Gout: an old disease in new perspective — a review.
      Hyperuricemia is known to increase the risk of gout attacks
      • Shoji A.
      • Yamanaka H.
      • Kamatani N.
      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.
      and incidence of uric acid kidney stones.
      • Roughley M.J.
      • Belcher J.
      • Mallen C.D.
      • Roddy E.
      Gout and risk of chronic kidney disease and nephrolithiasis: meta-analysis of observational studies.
      Consequently, therapeutic lowering of the serum uric acid level is the focus of the management of gout.
      • Claus L.W.
      • Saseen J.J.
      Patient considerations in the management of gout and role of combination treatment with lesinurad.
      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.
      • Sattui S.E.
      • Gaffo A.L.
      Treatment of hyperuricemia in gout: current therapeutic options, latest developments and clinical implications.
      Febuxostat is a selective non–purine based xanthine oxidase inhibitor that limits the production of uric acid.
      • Osada Y.
      • Tsuchimoto M.
      • Fukushima H.
      • et al.
      Hypouricemic effect of the novel xanthine oxidase inhibitor, TEI-6720, in rodents.
      ,
      • Takano Y.
      • Hase-Aoki K.
      • Horiuchi H.
      • et al.
      Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase.
      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
      • White W.B.
      • Saag K.G.
      • Becker M.A.
      • et al.
      Cardiovascular safety of febuxostat or allopurinol in patients with gout.
      that led to a boxed warning by the US Food and Drug Administration in 2019.
      US Food and Drug Administration
      FDA adds boxed warning for increased risk of death with gout medicine Uloric (febuxostat).
      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
      • Cuenca J.A.
      • Balda J.
      • Palacio A.
      • Young L.
      • Pillinger M.H.
      • Tamariz L.
      Febuxostat and cardiovascular events: a systematic review and 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
      • Higgins J.P.T.
      • Altman D.G.
      • Gotzsche P.C.
      • et al.
      The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials.
      and reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis protocols.
      • Shamseer L.
      • Moher D.
      • Clarke M.
      • et al.
      Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation.
      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
      • Jadad A.R.
      • Moore R.A.
      • Carroll D.
      • et al.
      Assessing the quality of reports of randomized clinical trials: is blinding necessary?.
      (Supplemental Table 1, available online at http://www.mcpiqojournal.org), and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (GRADEpro GDT),
      GRADEpro
      GRADE your evidence and improve your guideline development in health care.
      which was classified as high, moderate, low, or very low (Supplemental Tables 2 and 3, available online at http://www.mcpiqojournal.org).
      • Guyatt G.
      • Oxman A.D.
      • Akl E.A.
      • et al.
      GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables.
      The risk of bias assessment was determined using the Cochrane risk of bias scale (Supplemental Figure 1, available online at http://www.mcpiqojournal.org). Publication bias was assessed using funnel plot (Supplemental Figure 2, available online at http://www.mcpiqojournal.org), and Egger’s regression test.

      Outcomes of Interest

      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.
      • Borenstein M.
      • Hedges L.V.
      • Higgins J.P.
      • Rothstein H.R.
      lntroduction to Meta-Analysis.
      (Supplemental Figure 3, available online at http://www.mcpiqojournal.org). This meta-analysis was 100% powered for primary endpoints.
      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).
      • White W.B.
      • Saag K.G.
      • Becker M.A.
      • et al.
      Cardiovascular safety of febuxostat or allopurinol in patients with gout.
      ,
      • Becker M.A.
      • Schumacher H.R.
      • MacDonald P.A.
      • Lloyd E.
      • Lademacher C.
      Clinical efficacy and safety of successful longterm urate lowering with febuxostat or allopurinol in subjects with gout.
      • Mukri M.N.A.
      • Kong W.Y.
      • Mustafar R.
      • et al.
      Role of febuxostat in retarding progression of diabetic kidney disease with asymptomatic hyperuricemia: a 6-months open-label, randomized controlled trial.
      • Nakagomi A.
      • Saiki Y.
      • Noma S.
      • et al.
      Effects of febuxostat and allopurinol on the inflammation and cardiac function in chronic heart failure patients with hyperuricemia.
      • Saag K.G.
      • Becker M.A.
      • Whelton A.
      • et al.
      Efficacy and safety of febuxostat extended and immediate release in patients with gout and renal impairment: a phase III placebo-controlled study.
      • Saag K.G.
      • Whelton A.
      • Becker M.A.
      • MacDonald P.
      • Hunt B.
      • Gunawardhana L.
      Impact of Febuxostat on Renal Function in Gout Patients With Moderate-to-Severe Renal Impairment.
      • Schumacher H.R.
      • Becker M.A.
      • Wortmann R.L.
      • et al.
      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.
      • Becker M.A.
      • Schumacher H.R.
      • Espinoza L.R.
      • et al.
      The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial.
      • Becker M.A.
      • Schumacher H.R.J.
      • Wortmann R.L.
      • et al.
      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.
      • Dalbeth N.
      • Saag K.G.
      • Palmer W.E.
      • et al.
      Effects of febuxostat in early gout.
      • Gunawardhana L.
      • Becker M.A.
      • Whelton A.
      • Hunt B.
      • Castillo M.
      • Saag K.
      Efficacy and safety of febuxostat extended release and immediate release in patients with gout and moderate renal impairment: phase II placebo-controlled study.
      • Gunawardhana L.
      • McLean L.
      • Punzi H.A.
      • et al.
      Effect of Febuxostat on ambulatory blood pressure in subjects with hyperuricemia and hypertension: A Phase 2 randomized placebo-controlled study.
      • Huang X.
      • Du H.
      • Gu J.
      • et al.
      An allopurinol-controlled, multicenter, randomized, double-blind, parallel between-group, comparative study of febuxostat in Chinese patients with gout and hyperuricemia.
      • Kimura K.
      • Hosoya T.
      • Uchida S.
      • et al.
      Febuxostat therapy for patients with stage 3 CKD and asymptomatic hyperuricemia: a randomized trial.
      • Kojima S.
      • Matsui K.
      • Hiramitsu S.
      • et al.
      Febuxostat for Cerebral and Cardiorenovascular Events Prevention Study.
      Egger’s regression test did not detect significant publication bias (P (two-tailed) = .51).

      Characteristics of Trials and Participants

      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).
      Table 1Details of the Randomized Clinical Trials
      Study, yearNComparative treatmentStudy periodCountryFollow-up (mo)Population
      Becker et al, 2005
      • Becker M.A.
      • Schumacher H.R.J.
      • Wortmann R.L.
      • et al.
      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.
      760Febuxostat 80 mg vs febuxostat 120 mg vs allopurinolJuly 2002–February 2004United States and Canada12Gout and hyperuricemia
      Schumacher et al, 2008
      • Schumacher H.R.
      • Becker M.A.
      • Wortmann R.L.
      • et al.
      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.
      1072Febuxostat 80 mg vs febuxostat 120 mg vs febuxostat 240 mg vs allopurinol vs placeboFebruary 2003–April 2004United States6.4Gout
      Becker et al, 2009
      • Becker M.A.
      • Schumacher H.R.
      • MacDonald P.A.
      • Lloyd E.
      • Lademacher C.
      Clinical efficacy and safety of successful longterm urate lowering with febuxostat or allopurinol in subjects with gout.
      1086Febuxostat 80 mg vs febuxostat 120 mg vs allopurinolUnited States and Canada40Gout
      Becker et al, 2010
      • Becker M.A.
      • Schumacher H.R.
      • Espinoza L.R.
      • et al.
      The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial.
      2269Febuxostat 40 mg vs febuxostat 80 mg vs allopurinolUnited States6Gout
      Huang et al, 2014
      • Nakagomi A.
      • Saiki Y.
      • Noma S.
      • et al.
      Effects of febuxostat and allopurinol on the inflammation and cardiac function in chronic heart failure patients with hyperuricemia.
      516Febuxostat 40 mg vs febuxostat 80 mg vs allopurinolFebruary 2010–December 2010China6.4Gout
      Nagakomi et al, 2015
      • Nakagomi A.
      • Saiki Y.
      • Noma S.
      • et al.
      Effects of febuxostat and allopurinol on the inflammation and cardiac function in chronic heart failure patients with hyperuricemia.
      61Febuxostat 40 mg vs allopurinolSeptember 2011–April 2013Japan12Heart failure and hyperuricemia
      Saag et al, 2016
      • Saag K.G.
      • Whelton A.
      • Becker M.A.
      • MacDonald P.
      • Hunt B.
      • Gunawardhana L.
      Impact of Febuxostat on Renal Function in Gout Patients With Moderate-to-Severe Renal Impairment.
      96Febuxostat 30 mg twice daily vs Febuxostat 40–80 mg once daily vs placeboUnited States12Gout and chronic kidney disease
      Dalbeth et al, 2017
      • Dalbeth N.
      • Saag K.G.
      • Palmer W.E.
      • et al.
      Effects of febuxostat in early gout.
      314Febuxostat 40–80 mg vs placeboUnited States24Gout
      Gunawardhana et al, 2017
      • Gunawardhana L.
      • McLean L.
      • Punzi H.A.
      • et al.
      Effect of Febuxostat on ambulatory blood pressure in subjects with hyperuricemia and hypertension: A Phase 2 randomized placebo-controlled study.
      121Febuxostat 80 mg vs placeboUnited States1.5Hypertension and hyperuricemia
      Gunawardhana et al, 2018
      • Gunawardhana L.
      • Becker M.A.
      • Whelton A.
      • Hunt B.
      • Castillo M.
      • Saag K.
      Efficacy and safety of febuxostat extended release and immediate release in patients with gout and moderate renal impairment: phase II placebo-controlled study.
      189Febuxostat IR 40 mg vs febuxostat XR 40 mg vs febuxostat IR 80 mg vs febuxostat XR 80 mg vs placeboMay 2014–October 2015United States3Gout
      Kimura et al, 2018
      • Kimura K.
      • Hosoya T.
      • Uchida S.
      • et al.
      Febuxostat therapy for patients with stage 3 CKD and asymptomatic hyperuricemia: a randomized trial.
      443Febuxostat 10–40 mg vs placeboNovember 2012–January 2014Japan25Asymptomatic hyperuricemia and stage 3 chronic kidney disease
      Mukri et al, 2018
      • Mukri M.N.A.
      • Kong W.Y.
      • Mustafar R.
      • et al.
      Role of febuxostat in retarding progression of diabetic kidney disease with asymptomatic hyperuricemia: a 6-months open-label, randomized controlled trial.
      93Febuxostat 40 mg vs placeboMalaysia6Diabetic nephropathy (chronic kidney disease stage 3 and 4) and hyperuricemia
      White et al, 2018
      • White W.B.
      • Saag K.G.
      • Becker M.A.
      • et al.
      Cardiovascular safety of febuxostat or allopurinol in patients with gout.
      6190Febuxostat 40–80 mg vs allopurinolApril 2010–May 2017United States32Gout and previous cardiovascular events
      Kojima et al, 2019
      • Kojima S.
      • Matsui K.
      • Hiramitsu S.
      • et al.
      Febuxostat for Cerebral and Cardiorenovascular Events Prevention Study.
      1070Febuxostat 10–40 mg vs non-febuxostat group (allopurinol 100 mg given if serum uric acid was elevated)November 2013–October 2014Japan36Elderly 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
      Saag et al, 2019
      • Saag K.G.
      • Becker M.A.
      • Whelton A.
      • et al.
      Efficacy and safety of febuxostat extended and immediate release in patients with gout and renal impairment: a phase III placebo-controlled study.
      1790Febuxostat IR 40 mg vs febuxostat XR 40 mg vs febuxostat IR 80 mg vs febuxostat XR 80 mg vs placeboApril 2015–November 2016United States3Gout
      Table 2Baseline Characteristics of the Included Trials
      ALP = allopurinol; BMI = body mass index; CAD = coronary artery disease; DM = diabetes mellitus; ER = extended release; FBX = febuxostat; HTN = hypertension; IR = immediate release.
      Study, yearTrial arm, dosage (mg)NMalesAge ± SD, yPatient population, n
      DMHTNCADBMI
      Becker et al, 2005
      • Becker M.A.
      • Schumacher H.R.J.
      • Wortmann R.L.
      • et al.
      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.
      FBX, 8025624351.8±11.7171062332.7±6.1
      FBX, 12025124352.0±12.1171132832.3±5.7
      ALP, 30025324351.6 ± 12.6191122332.6±6.1
      Schumacher et al, 2008
      • Schumacher H.R.
      • Becker M.A.
      • Wortmann R.L.
      • et al.
      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.
      FBX, 8026725151±121243833±6
      FBX, 12026925551±121243733±7
      FBX, 24013412654±13702433±7
      ALP, 100-30026824952±121232733±6
      Placebo13412352±12611832±6
      Becker et al, 2009
      • Becker M.A.
      • Schumacher H.R.
      • MacDonald P.A.
      • Lloyd E.
      • Lademacher C.
      Clinical efficacy and safety of successful longterm urate lowering with febuxostat or allopurinol in subjects with gout.
      FBX, 8064951.4±11.95462957132.3±5.78
      FBX, 12029250.9±11.57151153333.2±6.17
      ALP, 30014551.0±11.3012731433.8±6.79
      Becker et al, 2010
      • Becker M.A.
      • Schumacher H.R.
      • Espinoza L.R.
      • et al.
      The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial.
      FBX, 4075772252.5±11.688942132.9±6.37
      FBX, 8075671053.0±11.7911344032.9±6.39
      ALP, 200–30075670952.9±11.7311043632.7±6.23
      Huang et al, 2014
      • Huang X.
      • Du H.
      • Gu J.
      • et al.
      An allopurinol-controlled, multicenter, randomized, double-blind, parallel between-group, comparative study of febuxostat in Chinese patients with gout and hyperuricemia.
      FBX, 4017216746.12±10.90545725.63±2.80
      FBX, 8017216947.40±11.18454725.25±2.64
      ALP, 30017216846.17±11.56444525.44±2.53
      Nakagomi et al, 2015
      • Nakagomi A.
      • Saiki Y.
      • Noma S.
      • et al.
      Effects of febuxostat and allopurinol on the inflammation and cardiac function in chronic heart failure patients with hyperuricemia.
      FBX, 40312269.3±109272023.6±2.4
      ALP, 100-300301871.8±812302423.1±3.1
      Saag et al, 2016
      • Saag K.G.
      • Whelton A.
      • Becker M.A.
      • MacDonald P.
      • Hunt B.
      • Gunawardhana L.
      Impact of Febuxostat on Renal Function in Gout Patients With Moderate-to-Severe Renal Impairment.
      FBX, 30 (twice daily)322567.3±11.11123032.8±6.45
      FBX, 40–80 (once daily)322663.6±8.15153134.2±7.30
      Placebo322666.3±12.05163133.3±6.36
      Dalbeth et al, 2017
      • Dalbeth N.
      • Saag K.G.
      • Palmer W.E.
      • et al.
      Effects of febuxostat in early gout.
      FBX, 40–8015714550.1±11.732.3±6.23
      Placebo15714351.4±12.433.1±6.40
      Gunawardhana et al, 2017
      • Gunawardhana L.
      • McLean L.
      • Punzi H.A.
      • et al.
      Effect of Febuxostat on ambulatory blood pressure in subjects with hyperuricemia and hypertension: A Phase 2 randomized placebo-controlled study.
      FBX, 80615052.2±10.54331.99±5.13
      a ALP = allopurinol; BMI = body mass index; CAD = coronary artery disease; DM = diabetes mellitus; ER = extended release; FBX = febuxostat; HTN = hypertension; IR = immediate release.

      Cardiovascular Mortality and All-Cause Mortality

      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 thumbnail gr2
      Figure 2(A) Forest plot of cardiovascular mortality. (B) Forest plot of all-cause mortality. M = Mantel; H = Haenszel.

      Cardiovascular Outcomes

      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 4 A 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.
      • Foody J.
      • Turpin R.S.
      • Tidwell B.A.
      • Lawrence D.
      • Schulman K.L.
      Major cardiovascular events in patients with gout and associated cardiovascular disease or heart failure and chronic kidney disease initiating a xanthine oxidase inhibitor.
      ,
      • Singh J.A.
      • Ramachandaran R.
      • Yu S.
      • Curtis J.R.
      Allopurinol use and the risk of acute cardiovascular events in patients with gout and diabetes.
      This cardioprotective effect could be attributed to the lower frequent of gout flares which has a detrimental effect on the cardiovascular system.
      • Krishnan E.
      Inflammation, oxidative stress and lipids: the risk triad for atherosclerosis in gout.
      On the other hand, using data from an observational cohort study from Taiwan, Su et al
      • Su C.-Y.
      • Shen L.-J.
      • Hsieh S.-C.
      • Lin L.-Y.
      • Lin F.-J.
      Comparing cardiovascular safety of febuxostat and allopurinol in the real world: a population-based cohort study.
      found a significant increased risk of adverse cardiovascular events and mortality with febuxostat and the association was dose dependent. In 2018, White et al
      • White W.B.
      • Saag K.G.
      • Becker M.A.
      • et al.
      Cardiovascular safety of febuxostat or allopurinol in patients with gout.
      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.
      • White W.B.
      • Saag K.G.
      • Becker M.A.
      • et al.
      Cardiovascular safety of febuxostat or allopurinol in patients with gout.
      The mechanism behind any potential risks is unknown. Experimental trials have reported no cardiac toxic effect on both heart function and rhythm.
      • Hou M.
      • Hu Q.
      • Chen Y.
      • Zhao L.
      • Zhang J.
      • Bache R.J.
      Acute effects of febuxostat, a nonpurine selective inhibitor of xanthine oxidase, in pacing induced heart failure.
      • Grewal H.K.
      • Martinez J.R.
      • Espinoza L.R.
      Febuxostat: drug review and update.
      • Zhao L.
      • Roche B.M.
      • Wessale J.L.
      • et al.
      Chronic xanthine oxidase inhibition following myocardial infarction in rabbits: effects of early versus delayed treatment.
      Furthermore, the rates of MI, arrhythmias, and MACE were similar in both groups of the CARES trial and this was consistent with our analysis.
      A recent meta-analysis
      • Cuenca J.A.
      • Balda J.
      • Palacio A.
      • Young L.
      • Pillinger M.H.
      • Tamariz L.
      Febuxostat and cardiovascular events: a systematic review and meta-analysis.
      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.
      • Walter S.D.
      Choice of effect measure for epidemiological data.

      Study Limitations

      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,
      • Cuenca J.A.
      • Balda J.
      • Palacio A.
      • Young L.
      • Pillinger M.H.
      • Tamariz L.
      Febuxostat and cardiovascular events: a systematic review and 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.
      • White W.B.
      • Saag K.G.
      • Becker M.A.
      • et al.
      Cardiovascular safety of febuxostat or allopurinol in patients with gout.
      ,
      • Nakagomi A.
      • Saiki Y.
      • Noma S.
      • et al.
      Effects of febuxostat and allopurinol on the inflammation and cardiac function in chronic heart failure patients with hyperuricemia.
      ,
      • Gunawardhana L.
      • McLean L.
      • Punzi H.A.
      • et al.
      Effect of Febuxostat on ambulatory blood pressure in subjects with hyperuricemia and hypertension: A Phase 2 randomized placebo-controlled study.
      ,
      • Kojima S.
      • Matsui K.
      • Hiramitsu S.
      • et al.
      Febuxostat for Cerebral and Cardiorenovascular Events Prevention Study.
      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)
      • MacDonald TM, Ford I, Nuki G, et al
      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.

      Supplemental Online Material

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