Effects of Xanthine Oxidase Inhibition in Hyperuricemic Heart Failure Patients: The Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (EXACT-HF) Study

Michael M Givertz, Kevin J Anstrom, Margaret M Redfield, Anita Deswal, Haissam Haddad, Javed Butler, W H Wilson Tang, Mark E Dunlap, Martin M LeWinter, Douglas L Mann, G Michael Felker, Christopher M O'Connor, Steven R Goldsmith, Elizabeth O Ofili, Mitchell T Saltzberg, Kenneth B Margulies, Thomas P Cappola, Marvin A Konstam, Marc J Semigran, Steven E McNulty, Kerry L Lee, Monica R Shah, Adrian F Hernandez, NHLBI Heart Failure Clinical Research Network, E Braunwald, N Lakdawala, S Jones, L Stevenson, K Brooks, S Anello, T Schuchard, J Humbert, A Diaz, I Roy, A DiSabatino, R Starling, P Bouscher, A Kono, P Maher-Hines, P Adams, M Donahue, K Aristy, G Snell, K Boddicker, C Neva, P Eckman, D Wilder, R McKelvie, K Boyajian, B Bart, S Mackedanz, C Michel, N Lapointe, S Rubin, B Gallagher, R Small, S Pointer, G Lewis, D Cocca-Spofford, M Daher, H Chen, J Gatzke, S Milbrandt, N Giannetti, C Barber, M Dettmer, A Rahmatullah, E Kiserow, A Chee, A Kao, K Haffey, V Florea, D Rhode, N Racine, H Brown, J Cross, P Hauptman, E Weber, A Bove, F McGonagle, L Chadwick, G Huggins, G Jamieson, J Fang, M Scheutzow, T Meyer, P Hu, G Flaker, B Baer, A Baker, F Pickering, J Stehlik, M Whipple, G Ewald, J Flanagan, D Vaughan, J W Berg, B Greenberg, M R Johnson, J Johnson, K D Kennedy, J Parillo, M Penn, E A Rose, D Vaughan, J W Berg, D McNamara, J Parillo, E A Rose, R Virmani, R Tracy, G Lin, J Oh, E Velazquez, J Ibarra, A Mascette, P Desvigne-Nickens, A Agresti, D Bild, J Keleti, M Kwak, G Sopko, Michael M Givertz, Kevin J Anstrom, Margaret M Redfield, Anita Deswal, Haissam Haddad, Javed Butler, W H Wilson Tang, Mark E Dunlap, Martin M LeWinter, Douglas L Mann, G Michael Felker, Christopher M O'Connor, Steven R Goldsmith, Elizabeth O Ofili, Mitchell T Saltzberg, Kenneth B Margulies, Thomas P Cappola, Marvin A Konstam, Marc J Semigran, Steven E McNulty, Kerry L Lee, Monica R Shah, Adrian F Hernandez, NHLBI Heart Failure Clinical Research Network, E Braunwald, N Lakdawala, S Jones, L Stevenson, K Brooks, S Anello, T Schuchard, J Humbert, A Diaz, I Roy, A DiSabatino, R Starling, P Bouscher, A Kono, P Maher-Hines, P Adams, M Donahue, K Aristy, G Snell, K Boddicker, C Neva, P Eckman, D Wilder, R McKelvie, K Boyajian, B Bart, S Mackedanz, C Michel, N Lapointe, S Rubin, B Gallagher, R Small, S Pointer, G Lewis, D Cocca-Spofford, M Daher, H Chen, J Gatzke, S Milbrandt, N Giannetti, C Barber, M Dettmer, A Rahmatullah, E Kiserow, A Chee, A Kao, K Haffey, V Florea, D Rhode, N Racine, H Brown, J Cross, P Hauptman, E Weber, A Bove, F McGonagle, L Chadwick, G Huggins, G Jamieson, J Fang, M Scheutzow, T Meyer, P Hu, G Flaker, B Baer, A Baker, F Pickering, J Stehlik, M Whipple, G Ewald, J Flanagan, D Vaughan, J W Berg, B Greenberg, M R Johnson, J Johnson, K D Kennedy, J Parillo, M Penn, E A Rose, D Vaughan, J W Berg, D McNamara, J Parillo, E A Rose, R Virmani, R Tracy, G Lin, J Oh, E Velazquez, J Ibarra, A Mascette, P Desvigne-Nickens, A Agresti, D Bild, J Keleti, M Kwak, G Sopko

Abstract

Background: Oxidative stress may contribute to heart failure (HF) progression. Inhibiting xanthine oxidase in hyperuricemic HF patients may improve outcomes.

Methods and results: We randomly assigned 253 patients with symptomatic HF, left ventricular ejection fraction ≤40%, and serum uric acid levels ≥9.5 mg/dL to receive allopurinol (target dose, 600 mg daily) or placebo in a double-blind, multicenter trial. The primary composite end point at 24 weeks was based on survival, worsening HF, and patient global assessment. Secondary end points included change in quality of life, submaximal exercise capacity, and left ventricular ejection fraction. Uric acid levels were significantly reduced with allopurinol in comparison with placebo (treatment difference, -4.2 [-4.9, -3.5] mg/dL and -3.5 [-4.2, -2.7] mg/dL at 12 and 24 weeks, respectively, both P<0.0001). At 24 weeks, there was no significant difference in clinical status between the allopurinol- and placebo-treated patients (worsened 45% versus 46%, unchanged 42% versus 34%, improved 13% versus 19%, respectively; P=0.68). At 12 and 24 weeks, there was no significant difference in change in Kansas City Cardiomyopathy Questionnaire scores or 6-minute walk distances between the 2 groups. At 24 weeks, left ventricular ejection fraction did not change in either group or between groups. Rash occurred more frequently with allopurinol (10% versus 2%, P=0.01), but there was no difference in serious adverse event rates between the groups (20% versus 15%, P=0.36).

Conclusions: In high-risk HF patients with reduced ejection fraction and elevated uric acid levels, xanthine oxidase inhibition with allopurinol failed to improve clinical status, exercise capacity, quality of life, or left ventricular ejection fraction at 24 weeks.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00987415.

Keywords: allopurinol; clinical trial; heart failure; xanthine oxidase.

Conflict of interest statement

Disclosures: WHWT receives research support from NIH. GMF receives research support from NIH, Amgen, Novartis, Roche Diagnostics and Otsuka, and consulting fees from Amgen, Novartis, Roche Diagnostics, Otsuka, Trevena, Singulex, Medtronic and Celladon. KBM reports advisory committee membership for Novo Nordisk and AstraZeneca, and research support from Juventis Therapuetics, Celladon, Thoratec, Innolign Biomedical, LLC and NIH (HL105993, HL110338, HL113777). MAK receives research support or consultant fees from Merck, Otsuka, Novartis, Amgen, and Johnson & Johnson. AFH receives research support from Amgen, Bristol-Myers Squibb, GlaxoSmithKline and Novartis, and consulting fees from Amgen and Novartis. The remaining authors have no conflicts to disclose.

© 2015 American Heart Association, Inc.

Figures

Figure 1
Figure 1
Consort Diagram.
Figure 2
Figure 2
Primary composite clinical endpoint (A) and changes in uric acid levels at 12 and 24 weeks (B). P-value in figure 2A is based on the 1 degree-of-freedom Cochran-Mantel-Haenszel Statistic using Modified Ridit Scores. P-values in figure 2B are for the comparison of allopurinol week 12 or week 24 change from baseline vs. placebo based on analysis of covariance models using the 100 multiple imputation datasets.
Figure 2
Figure 2
Primary composite clinical endpoint (A) and changes in uric acid levels at 12 and 24 weeks (B). P-value in figure 2A is based on the 1 degree-of-freedom Cochran-Mantel-Haenszel Statistic using Modified Ridit Scores. P-values in figure 2B are for the comparison of allopurinol week 12 or week 24 change from baseline vs. placebo based on analysis of covariance models using the 100 multiple imputation datasets.
Figure 3
Figure 3
Secondary Endpoints: Changes in quality of life using the Kansas City Cardiomyopathy Questionnaire overall summary score (A) and sub-maximal exercise capacity using the 6-minute walk test (B) at 12 and 24 weeks. P-values are for the comparison of allopurinol week 12 or week 24 change from baseline vs. placebo based on analysis of covariance models using the 100 multiple imputation datasets.
Figure 3
Figure 3
Secondary Endpoints: Changes in quality of life using the Kansas City Cardiomyopathy Questionnaire overall summary score (A) and sub-maximal exercise capacity using the 6-minute walk test (B) at 12 and 24 weeks. P-values are for the comparison of allopurinol week 12 or week 24 change from baseline vs. placebo based on analysis of covariance models using the 100 multiple imputation datasets.
Figure 4
Figure 4
Risk of death or all-cause hospitalization (A) or heart failure hospitalization (B) using the Kaplan-Meier method.
Figure 4
Figure 4
Risk of death or all-cause hospitalization (A) or heart failure hospitalization (B) using the Kaplan-Meier method.

Source: PubMed

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