Abstract
Background
Hyperuricemia and gout are associated with an increased risk of cardiovascular disease
(CVD). It is unknown whether treating hyperuricemia with xanthine oxidase inhibitors
(XOIs), including allopurinol and febuxostat, modifies cardiovascular risks.
Methods
We used US insurance claims data to conduct a cohort study among gout patients, comparing
XOI initiators with non-users with hyperuricemia defined as serum uric acid level
≥6.8 mg/dL. We calculated incidence rates of a composite nonfatal cardiovascular outcome
that included myocardial infarction, coronary revascularization, stroke, and heart
failure. Propensity score (PS)-matched Cox proportional hazards regression compared
the risk of composite cardiovascular endpoint in XOI initiators vs those with untreated
hyperuricemia, controlling for baseline confounders. In a subgroup of patients with
uric acid levels available, PS-matched Cox regression further adjusted for baseline
uric acid levels.
Results
There were 24,108 PS-matched pairs with a mean age of 51 years and 88% male. The incidence
rate per 1000 person-years for composite CVD was 24.1 (95% confidence interval [CI]
22.6-26.0) in XOI initiators and 21.4 (95% CI, 19.8-23.2) in the untreated hyperuricemia
group. The PS-matched hazard ratio for composite CVD was 1.16 (95% CI, 0.99-1.34)
in XOI initiators vs those with untreated hyperuricemia. In subgroup analyses, the
PS-matched hazard ratio for composite CVD adjusted for serum uric acid levels was
1.10 (95% CI, 0.74-1.64) among XOI initiators.
Conclusions
Among patients with gout, initiation of XOI was not associated with an increased or
decreased cardiovascular risk compared with those with untreated hyperuricemia. Subgroup
analyses adjusting for baseline uric acid levels also showed no association between
XOI and cardiovascular risk.
Keywords
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References
- Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008.Arthritis Rheum. 2011; 63: 3136-3141
- Pathogenesis of gout.Ann Intern Med. 2005; 143: 499-516
- Gout in the UK and Germany: prevalence, comorbidities and management in general practice 2000-2005.Ann Rheum Dis. 2008; 67: 960-966
- Clinical and health care use characteristics of patients newly prescribed allopurinol, febuxostat and colchicine for gout.Arthritis Care Res (Hoboken). 2013; 65: 2008-2014
- Gout is associated with more comorbidities, poorer health-related quality of life and higher healthcare utilisation in US veterans.Ann Rheum Dis. 2008; 67: 1310-1316
- Comorbidities of gout and hyperuricemia in the US general population: NHANES 2007-2008.Am J Med. 2012; 125: 679-687
- Hyperuricemia and incident hypertension: a systematic review and meta-analysis.Arthritis Care Res (Hoboken). 2011; 63: 102-110
- Hyperuricemia and risk of stroke: a systematic review and meta-analysis.Arthritis Rheum. 2009; 61: 885-892
- Hyperuricemia and coronary heart disease: a systematic review and meta-analysis.Arthritis Care Res (Hoboken). 2010; 62: 170-180
- 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia.Arthritis Care Res (Hoboken). 2012; 64: 1431-1446
- Allopurinol as a cardiovascular drug.Cardiol Rev. 2011; 19: 265-271
- Changes in uric acid levels and allopurinol use in chronic heart failure: association with improved survival.J Card Fail. 2012; 18: 694-701
Grimaldi-Bensouda L, Alpérovitch A, Aubrun E, et al. Impact of allopurinol on risk of myocardial infarction. Ann Rheum Dis, in press.
- Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial.JAMA. 2008; 300: 924-932
- Effect of allopurinol on cardiovascular incidence among hypertensive nephropathy patients: the Gonryo study.Clin Exp Nephrol. 2012; 17: 554
- Impact of allopurinol use on urate concentration and cardiovascular outcome.Br J Clin Pharmacol. 2011; 71: 600-607
- Xanthine oxidase inhibition for hyperuricemic heart failure patients: design and rationale of the EXACT-HF study.Circ Heart Fail. 2013; 6: 862-868
- Gout, allopurinol use, and heart failure outcomes.Arch Intern Med. 2010; 170: 1358-1364
- Febuxostat: a new treatment for hyperuricaemia in gout.Rheumatology (Oxford). 2009; 48: ii15-ii19
- 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.Arthritis Rheum. 2008; 59: 1540-1548
- A systematic review of validated methods for identifying cerebrovascular accident or transient ischemic attack using administrative data.Pharmacoepidemiol Drug Saf. 2012; 21: 100-128
- A systematic review of validated methods for identifying heart failure using administrative data.Pharmacoepidemiol Drug Saf. 2012; 21: 129-140
- Accuracy of Medicare claims-based diagnosis of acute myocardial infarction: estimating positive predictive value on the basis of review of hospital records.Am Heart J. 2004; 148: 99-104
- An algorithm to identify incident myocardial infarction using Medicaid data.Pharmacoepidemiol Drug Saf. 2009; 18: 1064-1071
- A combined comorbidity score predicted mortality in elderly patients better than existing scores.J Clin Epidemiol. 2011; 64: 749-759
- Estimating causal effects from large data sets using propensity scores.Ann Intern Med. 1997; 127: 757-763
- The performance of different propensity score methods for estimating marginal odds ratios.Stat Med. 2007; 26: 3078-3094
- Some methods of propensity-score matching had superior performance to others: results of an empirical investigation and Monte Carlo simulations.Biom J. 2009; 51: 171-184
- Covariate selection in high-dimensional propensity score analyses of treatment effects in small samples.Am J Epidemiol. 2011; 173: 1404-1413
- High-dimensional propensity score adjustment in studies of treatment effects using health care claims data.Epidemiology. 2009; 20: 512-522
- Evaluating the proportional hazards Assumption.in: Gail M. Krickberg K. Samet J. Tsiatis A. Wong W. Survival Analysis: A Self-Learning Text. 3rd ed. Springer, New York2012
- Supplementing claims data with outpatient laboratory test results to improve confounding adjustment in effectiveness studies of lipid-lowering treatments.BMC Med Res Methodol. 2012; 12: 180
- Impact of noncompliance with urate-lowering drug on serum urate and gout-related healthcare costs: administrative claims analysis.Curr Med Res Opin. 2009; 25: 1711-1719
- Primary care providers' knowledge, beliefs and treatment practices for gout: results of a physician questionnaire.Rheumatology (Oxford). 2013; 52: 1623-1629
- Evaluating medication effects outside of clinical trials: new-user designs.Am J Epidemiol. 2003; 158: 915-920
- A randomized study of allopurinol on endothelial function and estimated glomular filtration rate in asymptomatic hyperuricemic subjects with normal renal function.Clin J Am Soc Nephrol. 2011; 6: 1887-1894
- Effect of the treatment with allopurinol on the endothelial function in patients with hyperuricemia.Endocr Res. 2012; 37: 1-6
- Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies.Circulation. 2002; 105: 2619-2624
- Allopurinol attenuates left ventricular remodeling and dysfunction after experimental myocardial infarction: a new action for an old drug?.Circulation. 2004; 110: 2175-2179
Article info
Publication history
Published online: February 03, 2015
Footnotes
Funding: SCK is supported by National Institutes of Health (NIH) grant K23 AR059677; received research support from Pfizer; and received tuition support for the Pharmacoepidemiology Program at the Harvard School of Public Health, partially funded by the Pharmaceutical Research and Manufacturers of America (PhRMA) foundation. SS is principal investigator of the Harvard-Brigham Drug Safety and Risk Management Research Center funded by the U.S. Food and Drug Administration (FDA); his work is partially funded by grants/contracts from the Patient-Centered Outcomes Research Institute, FDA, and National Heart, Lung, and Blood Institute (NHLBI). NC is supported by research grants from CVS Caremark, Aetna, the Commonwealth Fund, the Robert Wood Johnson Foundation, Merck, NHLBI, the Agency for Healthcare Research and Quality, FDA, and the PhRMA, all unrelated to the subject of the present study. RJG receives research grants from the NIH, AstraZeneca and Novartis. DHS is supported by NIH grants K24 AR055989, P60 AR047782, and R01 AR056215; and receives research support through grants from Amgen, Lilly, and Pfizer.
Conflict of Interest: SS is consultant to WHISCON, LLC and to Aetion, Inc., of which he also owns shares; and is principal investigator of investigator-initiated grants to the Brigham and Women's Hospital from Novartis and Boehringer-Ingelheim, unrelated to the topic of this study. NC received consulting fees from Mercer Health and Benefits, the Alosa Foundation, and CVS Caremark. DHS serves in unpaid roles on studies sponsored by Pfizer, Novartis, Lilly, and Bristol Myers Squibb; and receives royalties from UpToDate.com.
Authorship: SCK had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. She is the guarantor for the study. All authors conceived and designed the study, analyzed and interpreted the data, and critically revised the manuscript for important intellectual content. SCK drafted the manuscript.
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© 2015 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
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- Effects of Xanthine Oxidase Inhibitors on Cardiovascular Disease in Patients with Gout: Ascertaining the Efficacy of Treatment MattersThe American Journal of MedicineVol. 128Issue 9
- PreviewWe read with interest the article by Kim et al1 about the potential effect of xanthine oxidase inhibitors in reducing cardiovascular events in patients with gout. In this cohort study using a claims database, the authors found a similar incidence rate of cardiovascular events in patients with gout under xanthine oxidase inhibitor treatment compared with matched, untreated patients with gout. The authors discussed the potential explanations for this result, such as a short follow-up period (1.4 years), an irregular adherence to the xanthine oxidase inhibitors, or the possibility that there is no causal relationship between gout and cardiovascular disease.
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