Allopurinol and peripheral vascular disease: enough observational data to warrant interventional studies: Allopurinol and the prevention of vascular disease

Allopurinol and peripheral vascular disease: enough observational data to warrant interventional... This editorial refers to Allopurinol and the risk of incident peripheral arterial disease in the elderly: a US Medicare claims data study by Jasvinder A. Singh and John Cleveland on pages 451–61.  Allopurinol has been approved for gout for five decades. Not until this century have we had sufficient high-quality clinical studies in gout therapeutics to confirm the benefits of a target serum urate and to determine optimal dosing regimens. Now there may be indications for allopurinol treatment on diseases other than gout on the horizon. In this issue of Rheumatology, a retrospective cohort study of older Americans explored the effect of allopurinol treatment on incident peripheral arterial disease (PAD) [1]. Allopurinol use was associated with a 12% risk reduction of new onset peripheral vascular disease, independent of other cardiovascular risk factors, with the benefit seen with durations of allopurinol use over 6 months. Gout and hyperuricaemia have been shown to be risk factors for PAD [2, 3] and allopurinol use has been associated with lower risk of myocardial infarction and stroke [4, 5]. Based on these observations Singh and Cleveland proposed that in the elderly allopurinol use, and duration of allopurinol use, would be associated with the reduction of new onset PAD. To test this hypothesis, they undertook a new user study in the 5% Medicare sample 2006–12. The new user pharmacoepidemiological study design aims to avoid the bias inherent in prevalent medication use studies [6]. In prevalent use studies, selection bias occurs as people that remain on medications may be healthy adherent and undertake other healthful behaviours while people that discontinue medications may be frailer than those that continue. In a retrospective cohort study using a new user design, the aim is to isolate the medication effect by observing from the start of use, thus aligning all participants exposed to a medication and establishing the temporal exposure to that medication. In Singh and Cleveland’s new user study, the target sample was Medicare beneficiaries over 65 years of age who received a prescription of allopurinol for at least 90 days, with no prescription in the prior year. Continuous use of allopurinol was determined by a second prescription of allopurinol within 120 days of the first, accounting for less than perfect adherence and left-over medication. In total 25 282 Medicare beneficiaries from the 2006 to 2012 5% Medicare sample were identified who met the new use of allopurinol definition and had no PAD in the previous year. The outcome of interest, onset of PAD, was captured by relevant ICD-9-CM codes. Follow-up continued until occurrence of PAD, loss of Medicare coverage, death or the end of the study period in 2012. In new users of allopurinol, 12% had new occurrence of PAD during follow-up. In a multivariable-adjusted analysis, allopurinol use was associated with a hazard ratio of 0.88 for incident PAD during follow-up, representing a 12% reduction in expected risk. Longer allopurinol use durations were associated with lower incidence of PAD when compared with no use of allopurinol, specifically 6 months to 2 years (12% reduction) and >2 years (25% reduction), while use of <6 months had no reduced risk of PAD. These intriguing observations raise the possibility that allopurinol (or possibly other urate lowering therapy), an inexpensive medication with a well-characterized adverse effect profile, may have benefits for prevention of PAD, a costly and burdensome condition. There are a number of limitations of this study that must be considered. Although the new user design creates a mechanism for retrospectively examining the effects of an intervention, there is considerable risk of bias. One source of bias is confounding by indication, potentially reduced by use of an active comparator, for example, colchicine [6]. However in this study, the reference group were people who were not prescribed allopurinol, so confounding by indication remains a concern. Although many possible confounders were included in the multivariate analysis, since no information about the reference group was provided, it is not clear whether the reference group were different from the prescribed group, including the absolute risk of PAD in these subjects. Interpretation of the results would be facilitated by a description of the reference population. In particular, renal impairment was not included in the models, which is potentially problematic since people with severe renal impairment may be less likely to be prescribed allopurinol and have a higher risk of PAD. The validity of these results is supported by similar reduction in risk of other atherosclerotic vascular disorders such as incident coronary arterial disease and ischaemic stroke in this population with new use of allopurinol [4, 5]. Mechanistic studies are required to determine how the risk is reduced, which has been proposed to be a dual effect of urate-lowering and the antioxidant benefits of allopurinol, although it is relevant to note that other anti-oxidants have failed to demonstrate benefit for vascular disease in randomized controlled trials. In parallel with biomechanistic studies, prospective interventional studies will be required to provide less biased evidence that allopurinol treatment provides benefits against cardiovascular events, with an acceptable adverse effect profile. Study design may be challenging, as large sample sizes are likely to be required in lower risk populations and enrolling higher risk patients is challenging as co-morbidities may exclude many from trials. It is likely that huge, multicentre studies will be required. Other tantalising possibilities include big-data analytics: the so called big-data-clinical trial [7]. A meta-analysis of 18 randomized controlled trials of urate-lowering agents that also reported cardiovascular adverse events did not confirm any beneficial effect on cardiovascular outcomes, although studies were not powered to examine this outcome [8]. Clearly more data are required. This study adds to the growing body of circumstantial evidence that allopurinol may be protective in vascular disease and interventional studies are now required. However, as well as considering new indications for allopurinol, there is an urgent need for efforts to promote optimal use of allopurinol for its principle indication: urate lowering therapy in gout, which is frequently suboptimal [9]. No longer can we simply see our role as solely prescribing medication: adherence to allopurinol is poor and research efforts have not focused sufficiently on understanding why this is so or how to address it. Considerable work in knowledge translation science should also be invested in gout management. The last decades of gout research have been exciting, with new insights on a common disease that was the ugly step-sister of the auto-immune arthritides. The association of gout with cardiovascular disease and the metabolic syndrome means insights may shed light on therapeutic opportunities for a much wider section of the population. The good science must continue. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: W.J.T. has received honorarium from Pfizer (NZ) for advisory board membership (<NZD10 000). The other author has declared no conflicts of interest. References 1 Singh JA, Cleveland J. Allopurinol and the risk of incident peripheral arterial disease in the elderly: a US Medicare claims data study. Rheumatology  2018; 57: 451– 61. 2 Clarson LE, Hider SL, Belcher J et al.   Increased risk of vascular disease associated with gout: a retrospective, matched cohort study in the UK Clinical Practice Research Datalink. Ann Rheum Dis  2015; 74: 642– 7. Google Scholar CrossRef Search ADS PubMed  3 Baker JF, Schumacher HR, Krishnan E. Serum uric acid level and risk for peripheral arterial disease: analysis of data from the multiple risk factor intervention trial. Angiology  2007; 58: 450– 7. Google Scholar CrossRef Search ADS PubMed  4 Singh JA, Yu S. Allopurinol and the risk of stroke in older adults receiving medicare. BMC Neurol  2016; 16: 1– 9. Google Scholar CrossRef Search ADS PubMed  5 Singh JA, Yu S. Allopurinol reduces the risk of myocardial infarction (MI) in the elderly: a study of Medicare claims. Arthritis Res Ther  2016; 18: 1– 11. Google Scholar CrossRef Search ADS PubMed  6 Lund JL, Richardson DB, Stürmer T. The active comparator, new user study design in pharmacoepidemiology: historical foundations and contemporary application. Curr Epidemiol Rep  2015; 2: 221– 8. Google Scholar CrossRef Search ADS PubMed  7 Raghupathi W, Raghupathi V. Big data analytics in healthcare: promise and potential. Health Inf Sci Syst  2014; 2: 3. Google Scholar CrossRef Search ADS PubMed  8 Zhang T, Pope JE. Cardiovascular effects of urate-lowering therapies in patients with chronic gout: a systematic review and meta-analysis. Rheumatology  2017; 56: 1144– 53. Google Scholar CrossRef Search ADS PubMed  9 Dalbeth N, Merriman TR, Stamp LK. Gout. Lancet  2016; 388: 2039– 52. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

Allopurinol and peripheral vascular disease: enough observational data to warrant interventional studies: Allopurinol and the prevention of vascular disease

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Abstract

This editorial refers to Allopurinol and the risk of incident peripheral arterial disease in the elderly: a US Medicare claims data study by Jasvinder A. Singh and John Cleveland on pages 451–61.  Allopurinol has been approved for gout for five decades. Not until this century have we had sufficient high-quality clinical studies in gout therapeutics to confirm the benefits of a target serum urate and to determine optimal dosing regimens. Now there may be indications for allopurinol treatment on diseases other than gout on the horizon. In this issue of Rheumatology, a retrospective cohort study of older Americans explored the effect of allopurinol treatment on incident peripheral arterial disease (PAD) [1]. Allopurinol use was associated with a 12% risk reduction of new onset peripheral vascular disease, independent of other cardiovascular risk factors, with the benefit seen with durations of allopurinol use over 6 months. Gout and hyperuricaemia have been shown to be risk factors for PAD [2, 3] and allopurinol use has been associated with lower risk of myocardial infarction and stroke [4, 5]. Based on these observations Singh and Cleveland proposed that in the elderly allopurinol use, and duration of allopurinol use, would be associated with the reduction of new onset PAD. To test this hypothesis, they undertook a new user study in the 5% Medicare sample 2006–12. The new user pharmacoepidemiological study design aims to avoid the bias inherent in prevalent medication use studies [6]. In prevalent use studies, selection bias occurs as people that remain on medications may be healthy adherent and undertake other healthful behaviours while people that discontinue medications may be frailer than those that continue. In a retrospective cohort study using a new user design, the aim is to isolate the medication effect by observing from the start of use, thus aligning all participants exposed to a medication and establishing the temporal exposure to that medication. In Singh and Cleveland’s new user study, the target sample was Medicare beneficiaries over 65 years of age who received a prescription of allopurinol for at least 90 days, with no prescription in the prior year. Continuous use of allopurinol was determined by a second prescription of allopurinol within 120 days of the first, accounting for less than perfect adherence and left-over medication. In total 25 282 Medicare beneficiaries from the 2006 to 2012 5% Medicare sample were identified who met the new use of allopurinol definition and had no PAD in the previous year. The outcome of interest, onset of PAD, was captured by relevant ICD-9-CM codes. Follow-up continued until occurrence of PAD, loss of Medicare coverage, death or the end of the study period in 2012. In new users of allopurinol, 12% had new occurrence of PAD during follow-up. In a multivariable-adjusted analysis, allopurinol use was associated with a hazard ratio of 0.88 for incident PAD during follow-up, representing a 12% reduction in expected risk. Longer allopurinol use durations were associated with lower incidence of PAD when compared with no use of allopurinol, specifically 6 months to 2 years (12% reduction) and >2 years (25% reduction), while use of <6 months had no reduced risk of PAD. These intriguing observations raise the possibility that allopurinol (or possibly other urate lowering therapy), an inexpensive medication with a well-characterized adverse effect profile, may have benefits for prevention of PAD, a costly and burdensome condition. There are a number of limitations of this study that must be considered. Although the new user design creates a mechanism for retrospectively examining the effects of an intervention, there is considerable risk of bias. One source of bias is confounding by indication, potentially reduced by use of an active comparator, for example, colchicine [6]. However in this study, the reference group were people who were not prescribed allopurinol, so confounding by indication remains a concern. Although many possible confounders were included in the multivariate analysis, since no information about the reference group was provided, it is not clear whether the reference group were different from the prescribed group, including the absolute risk of PAD in these subjects. Interpretation of the results would be facilitated by a description of the reference population. In particular, renal impairment was not included in the models, which is potentially problematic since people with severe renal impairment may be less likely to be prescribed allopurinol and have a higher risk of PAD. The validity of these results is supported by similar reduction in risk of other atherosclerotic vascular disorders such as incident coronary arterial disease and ischaemic stroke in this population with new use of allopurinol [4, 5]. Mechanistic studies are required to determine how the risk is reduced, which has been proposed to be a dual effect of urate-lowering and the antioxidant benefits of allopurinol, although it is relevant to note that other anti-oxidants have failed to demonstrate benefit for vascular disease in randomized controlled trials. In parallel with biomechanistic studies, prospective interventional studies will be required to provide less biased evidence that allopurinol treatment provides benefits against cardiovascular events, with an acceptable adverse effect profile. Study design may be challenging, as large sample sizes are likely to be required in lower risk populations and enrolling higher risk patients is challenging as co-morbidities may exclude many from trials. It is likely that huge, multicentre studies will be required. Other tantalising possibilities include big-data analytics: the so called big-data-clinical trial [7]. A meta-analysis of 18 randomized controlled trials of urate-lowering agents that also reported cardiovascular adverse events did not confirm any beneficial effect on cardiovascular outcomes, although studies were not powered to examine this outcome [8]. Clearly more data are required. This study adds to the growing body of circumstantial evidence that allopurinol may be protective in vascular disease and interventional studies are now required. However, as well as considering new indications for allopurinol, there is an urgent need for efforts to promote optimal use of allopurinol for its principle indication: urate lowering therapy in gout, which is frequently suboptimal [9]. No longer can we simply see our role as solely prescribing medication: adherence to allopurinol is poor and research efforts have not focused sufficiently on understanding why this is so or how to address it. Considerable work in knowledge translation science should also be invested in gout management. The last decades of gout research have been exciting, with new insights on a common disease that was the ugly step-sister of the auto-immune arthritides. The association of gout with cardiovascular disease and the metabolic syndrome means insights may shed light on therapeutic opportunities for a much wider section of the population. The good science must continue. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: W.J.T. has received honorarium from Pfizer (NZ) for advisory board membership (<NZD10 000). The other author has declared no conflicts of interest. References 1 Singh JA, Cleveland J. Allopurinol and the risk of incident peripheral arterial disease in the elderly: a US Medicare claims data study. Rheumatology  2018; 57: 451– 61. 2 Clarson LE, Hider SL, Belcher J et al.   Increased risk of vascular disease associated with gout: a retrospective, matched cohort study in the UK Clinical Practice Research Datalink. Ann Rheum Dis  2015; 74: 642– 7. Google Scholar CrossRef Search ADS PubMed  3 Baker JF, Schumacher HR, Krishnan E. Serum uric acid level and risk for peripheral arterial disease: analysis of data from the multiple risk factor intervention trial. Angiology  2007; 58: 450– 7. Google Scholar CrossRef Search ADS PubMed  4 Singh JA, Yu S. Allopurinol and the risk of stroke in older adults receiving medicare. BMC Neurol  2016; 16: 1– 9. Google Scholar CrossRef Search ADS PubMed  5 Singh JA, Yu S. Allopurinol reduces the risk of myocardial infarction (MI) in the elderly: a study of Medicare claims. Arthritis Res Ther  2016; 18: 1– 11. Google Scholar CrossRef Search ADS PubMed  6 Lund JL, Richardson DB, Stürmer T. The active comparator, new user study design in pharmacoepidemiology: historical foundations and contemporary application. Curr Epidemiol Rep  2015; 2: 221– 8. Google Scholar CrossRef Search ADS PubMed  7 Raghupathi W, Raghupathi V. Big data analytics in healthcare: promise and potential. Health Inf Sci Syst  2014; 2: 3. Google Scholar CrossRef Search ADS PubMed  8 Zhang T, Pope JE. Cardiovascular effects of urate-lowering therapies in patients with chronic gout: a systematic review and meta-analysis. Rheumatology  2017; 56: 1144– 53. Google Scholar CrossRef Search ADS PubMed  9 Dalbeth N, Merriman TR, Stamp LK. Gout. Lancet  2016; 388: 2039– 52. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Journal

RheumatologyOxford University Press

Published: Mar 1, 2018

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