Skip to main content
Download PDF

Allopurinol reduces the risk of myocardial infarction (MI) in the elderly: a study of Medicare claims

Arthritis Research & Therapy volume 18, Article number: 209 (2016) Cite this article

Abstract

Background

Previous observational studies that have examined the association of allopurinol with myocardial infarction (MI) have provided contradictory results. One study showed that allopurinol reduced the risk, while another study showed an increased risk with allopurinol. Therefore, our objective was to assess whether allopurinol use is associated with a reduction in the risk of MI in the elderly.

Method

We used the 2006–2012 5 % random sample of Medicare beneficiaries to study the association of new allopurinol initiation and the risk of incident MI in a cohort study. Multivariable-adjusted Cox regression models adjusted for age, gender, race, and Charlson index, in addition to various cardio-protective medications (beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, diuretics, statins). We calculated hazard ratios (HRs) with 95 % confidence intervals (CIs). Sensitivity analyses adjusted for coronary artery disease (CAD) risk factors, including hypertension, hyperlipidemia, diabetes, and smoking.

Results

Of the 29,298 episodes of incident allopurinol use, 1544 were associated with incident MI (5.3 % episodes). Allopurinol use was associated with reduced hazards of MI, with a HR of 0.85 (95 % CI, 0.77 to 0.95). Compared to no allopurinol use, longer durations of allopurinol use were associated with a lower HR of MI: 1–180 days, 0.98 (95 % CI, 0.84 to 1.14); 181 days to 2 years, 0.83 (95 % CI, 0.72 to 0.95); and >2 years, 0.70 (95 % CI, 0.56 to 0.88). Other factors associated with a higher hazard of MI were: age 75 to <85 years and ≥85 years, male gender, higher Charlson index score, and the use of an ACE inhibitor. Adjustment for CAD risk factors confirmed these findings.

Conclusion

Incident allopurinol use was associated with a reduction in the risk of incident MI in the elderly. Longer durations of allopurinol use reduced the risk of incident MI incrementally. Future studies should assess the underlying mechanisms for MI prevention and assess the risk-benefit ratio for allopurinol use.

Background

Coronary artery disease (CAD) is the most common cardiovascular disease [1]. CAD is the leading cause of disability [2] and mortality worldwide [3]. Myocardial infarction (MI) is a common, acute manifestation of CAD [4]. The case fatality rate of MI remains high, despite a reduction over time [4, 5]. Thus, MI constitutes a significant public health burden.

Allopurinol is commonly used for the treatment of hyperuricemia [6, 7]. Allopurinol is a structural isomer of hypoxanthine, and its active metabolite, oxypurinol, competes with hypoxanthine for the enzyme xanthine oxidase, and leads to the lowering of uric acid production. In addition to its urate-lowering effect, recent studies have suggested other mechanisms of action, some dependent and some independent of this action [8–15]. Debate continues whether allopurinol use reduces the risk of MI and the magnitude of this effect.

Two studies that examined the association of allopurinol with MI provided contradictory results. In a population-based case-control study, de Abajo et al. [16] reported that allopurinol was associated with a lower risk of MI with a hazard ratio (HR) of 0.52. This contradicts the finding of an increased HR of 1.25 for a cardiovascular event requiring hospitalization (including MI, stroke, hypertension, etc.) with allopurinol use in a population-based study of patients with gout by Kok et al. [17]. Compared to the positive study with only MI as an outcome [16], the study by Kok et al. included a more diverse (composite) outcome, used a prevalent rather than an incident user design, and was limited to patients with gout [17]. The study by de Abajo et al. was limited to non-fatal MI and used a case-control design, which are important study limitations [16]. Thus, both studies had important limitations that make the interpretation of study results difficult. The contradictory findings leave an average reader unclear about whether allopurinol use reduces the risk of MI or not. To our knowledge, it is also not known whether the MI risk reduction with allopurinol varies by certain patient characteristics, such as age, gender, and race.

Therefore, our objective was to assess whether allopurinol use was associated with a reduction in the risk of MI in the elderly. We hypothesized that (1) allopurinol use and (2) allopurinol use duration will each be independently associated with a reduction in the risk of MI. We also explored whether MI risk reduction with allopurinol varies by age, gender, and race.

Methods

Study cohort and population of interest

This retrospective cohort study used claims data from the 5 % random sample of Medicare beneficiaries from 2006 to 2012. Data were obtained from the Centers for Medicare and Medicaid Services (CMS) Chronic Condition Data Warehouse. The insurance claims for each beneficiary including inpatient, outpatient, skilled nursing facility, noninstitutional provider, home health, hospice, durable medical equipment services, and prescription drugs were extracted alongside beneficiary’s demographic information. Eligible subjects for the cohort study were: Medicare beneficiaries who were 65 years of age or older; lived in the US; were enrolled continuously in traditional Medicare fee-for-service and pharmacy coverage (Parts A, B, and D) and not enrolled in Medicare Advantage Plan, who had new treatment with allopurinol (defined in the section below). The Institutional Review Board at the University of Alabama at Birmingham approved the study.

Exposure definition and covariates

We defined new allopurinol treatment as a new-filled allopurinol prescription, with no allopurinol prescription filled during a look-back baseline period of 365 days. Each day of observation within each episode was labeled as exposed or non-exposed based upon the days supply for allopurinol prescription in pharmacy records after the beginning of the episode. We allowed up to 30 days stock carry over. Patients were considered exposed for 30 days after the end of the days supply to capture the attributable events, after which a new continuous allopurinol exposure period started. We categorized allopurinol use duration as none, 1–180 days, 181 days to 2 years, and longer than 2 years. A patient could contribute multiple allopurinol treatment episodes during different time periods.

We obtained several covariates from the Medicare denominator file: age at the index date of each episode, gender, race/ethnicity, residence, and comorbidity scores in the baseline period for each allopurinol treatment episode, which were derived using Charlson-Romano comorbidity index score, a validated measure of medical comorbidity developed for claims data [18]. We also adjusted for the use of medications for cardiovascular diseases (beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, statins, and diuretics).

Outcome

The study outcome was incident MI, defined as the first incidence of MI during the study period after the initiation of a new allopurinol prescription, identified by the presence of International Classification of Diseases, ninth revision, common modification (ICD-9-CM) code, 410.x1. Patients had to have no MI in the baseline period of 365 days. The follow-up for each treatment episode began on the earliest allopurinol treatment initiation date during the study period and ended on the earliest of the first date of MI, the first date of losing full Medicare coverage, the date of death, or the end of the study (31 December 2012).

Statistical analyses

We calculated summary statistics for the cohort, by occurrence versus non-occurrence of MI, and by allopurinol exposure versus not. We performed Cox proportional hazard regression models to assess the association of incident allopurinol exposure (yes/no) or the duration of allopurinol use and incident MI. Multivariable analysis adjusted for age, gender, race, Charlson-Romano comorbidity score, and the use of medications for cardiovascular diseases (beta-blockers, ACE inhibitors, statins, and diuretics). We accounted for correlated episodes (patients could possibly contribute more than one episode of new allopurinol use) using the Huber-White “Sandwich” variance estimator [19] and calculated robust standard errors for all estimates. HRs and 95 % confidence intervals (CIs) were calculated.

Sensitivity analyses were performed adjusting for: 1) individual CAD risk factors including hypertension, hyperlipidemia, diabetes, and smoking, instead of Charlson-Romano comorbidity index; (2) additionally adjusting the previous sensitivity analyses for CAD and peripheral vascular disease (PVD); and (3) additionally adjusting the previous sensitivity analyses for aspirin and colchicine use.

In multivariable-adjusted subgroup analyses by age, gender, and race, the main model was adjusted for all factors (age, gender, race, Charlson-Romano comorbidity score, use of cardiovascular medications, allopurinol use or duration) except the factor of interest for each subgroup analysis, respectively (age, gender, race).

Results

Characteristics of the patient population

There were 29,298 episodes of incident allopurinol use, with no allopurinol use in the baseline period of 365 days (Table 1). Of these, 1544 allopurinol use episodes ended in an incident MI (5.3 % episodes), while the majority (94.7 %) did not (Fig. 1). Compared to incident allopurinol episodes that did not end in an MI, allopurinol episodes ending with an incident MI were associated with older age, a higher Charlson-Romano index (4.24 versus 2.98), male gender, and non-White race (Table 1). Table 2 shows MI incidence rate by allopurinol use and the duration of allopurinol use.

Table 1 Demographic and clinical characteristics of episodes of incident myocardial infarction* (MI) in allopurinol users
Full size table
Fig. 1
figure 1

Flow-chart of study cohort of incident allopurinol users from 2006 to 2012 for a baseline of 365 days. A + B + C-HMO, DC, MI myocardial infarction, Nb, NE number of episodes, Np, Number of prescriptions, Nb, Number of beneficiaries

Full size image
Table 2 Incidence rate of myocardial infarction (MI) with incident allopurinol exposure* (yes versus no) and different allopurinol use duration periods
Full size table

Allopurinol use, allopurinol duration, and the risk of myocardial infarction

In patients with a new MI, those using allopurinol were older and had a higher Charlson comorbidity index compared to patients not using allopurinol (Table 3). Univariate associations are shown in Table 4. In multivariable-adjusted analyses, allopurinol use was associated with 15 % reduction in hazard of MI, with a HR of 0.85 (95 % CI, 0.77 to 0.95). Other factors associated with higher hazard of MI were: age 75 to <85 years and ≥85 years, male gender, higher Charlson index score, and the use of an ACE inhibitor (Table 4).

Table 3 Demographic characteristics and prevalence of comorbidities by allopurinol use in episodes with incident myocardial infarction (MI)
Full size table
Table 4 Incident allopurinol use and the risk of incident myocardial infarction (MI)*
Full size table

In a separate multivariable-adjusted model, compared to no allopurinol use, we found that longer allopurinol use duration was associated with a lower hazard of MI: 181 days to 2 years, 0.83 (95 % CI, 0.72 to 0.95) and >2 years, 0.70 (95 % CI, 0.56 to 0.88) (Table 4); allopurinol use for 1–180 days was not associated with reduction in hazard of MI.

Sensitivity analyses limited to patients with gout showed that the findings were unchanged with minimal/no attenuation of HRs (Table 5); 83 % of allopurinol users had a diagnosis of gout. Sensitivity analyses were performed adjusting for CAD risk factors, i.e., hypertension, hyperlipidemia, diabetes, and smoking (instead of Charlson-Romano index), and these confirmed the main findings: allopurinol use, 0.86 (0.77, 0.95), and allopurinol use duration (1–180 days, 0.97 (0.83, 1.13); 181 days to 2 years, 0.84 (0.73, 0.97); and >2 years, 0.69 (0.55, 0.87)) were significantly associated. Additional file 1 shows this in more detail. Sensitivity analyses that adjusted for PVD and CAD in addition to CAD risk factors confirmed the associations of allopurinol use and duration of allopurinol use with MI risk, with no further attenuation of HRs (see Additional file 2). Sensitivity analyses that further adjusted for aspirin and colchicine use showed minimal/no attenuation of HRs for allopurinol use and allopurinol use duration; neither aspirin, nor colchicine were significant in this model that adjusted for other covariates including CAD and PVD (see Additional file 3).

Table 5 Incident allopurinol use and the risk of incident myocardial infarction (MI)* limited to patients with a diagnosis of gout
Full size table

Subgroup analyses by age, gender, and race for risk reduction by allopurinol use duration

In multivariable-adjusted subgroup analyses by age, gender, and race, allopurinol use durations of 181 days to 2 years and >2 years were associated with a reduction of hazard of MI, most evident for the age groups 65–74 and ≥85 years, male gender, and Blacks (Fig. 2).

Fig. 2
figure 2

Multivariable-adjusted hazard ratios of MI by duration of allopurinol use by a age group, b gender and c race. For the multivariable-adjusted subgroup analyses by age, gender, and race, the main model was adjusted for all factors (age, gender, race, and Charlson-Romano comorbidity score) except the factor of interest, respectively, which was used to perform stratified analysis (age, gender, race)

Full size image

Discussion

In this study of Medicare claims we found that allopurinol use was independently associated with a lower risk of an incident MI. Compared to patients who did not use allopurinol, new allopurinol users had a 15 % lower hazard of an incident MI. We also found that a longer duration of allopurinol use was associated with a greater risk reduction in hazard for an incident MI, i.e., allopurinol use durations of 0.5–2 years and >2 years was associated with a 17 % and 30 % reduced hazard of an incident MI. Our study provides robust evidence of MI risk reduction with allopurinol use and suggests that it may have a cardioprotective action. Several study findings merit further discussion.

In previous studies, allopurinol use was associated with a 48 % reduction in the hazard (HR, 0.52) for an incident non-fatal MI using a Spanish database [16] versus a 25 % increase in the hazard (HR, 1.25) of a cardiovascular event requiring hospitalization (including MI, hypertension, stroke, etc.) in Taiwanese patients with gout [17]. The study showing an increased risk included a composite cardiovascular outcome (more diverse than MI) and used a prevalent user (rather than an incident user) design, both of which may have led to the lack of observation of a protective effect for MI [17]. On the other hand, the study by de Abajo et al. showing a protective allopurinol effect used a case-control study with matching (a less robust study design) and was limited to non-fatal MI, but used an incident user design [16]. The contradictory evidence from two population-based studies indicated that more evidence that is robust was needed, which will be crucial in deciding whether allopurinol use reduces the risk of MI or not. Other studies have shown a beneficial effect of allopurinol use (versus non-use) on mortality [20–22], heart failure readmission or death [23], and overall cardiovascular outcomes (including, but not limited to, MI) in patients with chronic kidney disease [24]; however, none specifically assessed MI only. A randomized, placebo-controlled, crossover trial included 65 adults with angiographically documented CAD, a positive exercise tolerance test, and stable chronic angina pectoris and randomized them to allopurinol (600 mg per day) or placebo for 6 weeks before crossover [13]. Allopurinol statistically significantly increased the median time to ST depression versus placebo (p = 0.0002; difference 43 s) and median total exercise time versus placebo (p = 0.0003) [13] showing its cardioprotective effect, providing one potential mechanism of the benefit we demonstrated. Similarly, a study comparing allopurinol to placebo in heart failure failed to show any benefit of allopurinol to placebo in patients with reduced ejection fraction  [25].

Our finding of a reduction in the risk of MI with allopurinol use in the elderly is based on a rigorous methodological approach using an incident user design. Use of a representative sample, adjustment for multiple covariates and potential confounders, and the robustness of estimates in sensitivity analyses, leads us to believe that our study findings are likely accurate and support a potential cardioprotective effect of allopurinol. To our knowledge, our study is amongst the first studies in the elderly population that show that allopurinol use is associated with a reduction in the risk of MI.

The mechanism of reduction in MI risk with allopurinol may be multi-fold. The anti-oxidant action of allopurinol [26–32] may be responsible for improving cardiac contractile function and preventing MI, similar to its beneficial effect on the progression of post-ischemic cardiomyopathy in mice [33]. Allopurinol improves endothelial function in renal failure, diabetes, sleep apnea, and heart failure [8–12, 34–43], also confirmed in a recent meta-analysis [44]. These mechanisms may delay the progression of atherosclerosis and/or prevent plaque instability [45]. Clinically, allopurinol has an anti-ischemic action in patients with stable, chronic angina [13], is associated with a reduction in left ventricular mass in patients with diabetes [14] and heart disease [15], and with a reduction in blood pressure [46, 47], which are potential mechanisms for its cardioprotective action. Other mechanisms of action for allopurinol include decreased macrophage interleukin 1-beta (IL1β) secretion upon the activation of NLRP3 inflammasome [48, 49], and the impairment in CD36-mediated TLR4/6-IRAK4/1 signaling [50], mechanisms that may contribute to cardiac risk [51].

Another important study finding was that the duration of allopurinol use was associated with a dose-dependent reduction in MI risk. In particular, compared to non-use, longer allopurinol use duration of >6 months to 2 years and >2 years were each associated with an independent reduction in the hazard of MI of 17 % and 30 %, respectively (HRs, 0.83 and 0.70). Surprisingly, allopurinol use <6 month was not associated with any reduction in the risk of MI, which might indicate a threshold of 6-month use for preventing MI. The reduction in hazard showed a response-gradient, which provides further support for the protective effect of allopurinol on incident MI, seen previously where long-term allopurinol use was associated with a lower hazard of cardiovascular events (including MI) at 0.43 (95 % CI, 0.21–0.88; p = 0.02) in an open-label extension of a randomized study [52]. Thus, longer term allopurinol use seems to be cardioprotective in patients with gout. Further support for a dose-response relationship for allopurinol use duration for cardioprotection is evident by observations of lower mortality risk in heart failure patients [22] and lower MI risk in the general population [16] with high-dose compared to low-dose allopurinol use. Whether the risk/benefit ratio of allopurinol becomes favorable due to potential cardioprotection in patients with asymptomatic hyperuricemia (without gout) remains to be seen.

The greatest reductions in the hazard of MI with allopurinol exposure were noted in those aged 65–74 and ≥85 years, those of female gender, and those of Black race, another interesting finding which needs confirmation and further study. A greater benefit in the elderly and a racial minority is particularly interesting, since these groups are usually at higher risk of worse MI outcomes [53, 54].

Our study has several strengths and limitations. Despite our efforts to control for various confounders, our study is subject to potential residual confounding due to the cohort study design. To avoid this bias, we controlled for multiple potential confounders and performed multiple sensitivity analyses that supported the robustness of our findings. Second, our database lacked information on other risk factors, such as over the counter aspirin use, body mass index and diet components, which can be viewed as risk factors for MI; however, risk reduction was confirmed in analyses adjusted for other traditional CAD risk factors including hypertension, hyperlipidemia, diabetes, and smoking, and in models that additionally adjusted for aspirin use (by prescription), and other cardiac and gout medications. Third, the number of MI events may have been too low to detect statistical significance of findings in certain subgroups, i.e., type II error; availability of the entire dataset would likely have overcome this limitation. However, use of a national 5 % Medicare sample is a standard approach in epidemiological research [55, 56], and we had in excess of 1500 events for the main analyses. Limited resources prevented us from analyses of 100 % Medicare data.

Fourth, the Medicare data do not allow us to investigate why allopurinol was prescribed and, although we know that 83 % of allopurinol users in our study had a diagnosis of gout, specific reasons for its use are not known and likely included other conditions such as hyperuricemia without gout, metabolic syndrome, renal stones, tumor lysis syndrome, etc. However, regardless of the reason for allopurinol prescription, our observation of its beneficial effect is generalizable to all US elderly who use allopurinol. We also showed with sensitivity analyses that these effects were similar in magnitude for elderly Americans with gout who used allopurinol. Finally, these data are derived from Medicare, and can only be generalized to the US elderly population, not the US general population. Fifty percent of the elderly using allopurinol are female, which is different to the usual institutional cohorts of allopurinol users dominated by men, since these studies include patients from all age groups; however, our sample is that of all US elderly aged 65 years and older.

Strengths of the study included the use of a representative US population, the ability to control for the common MI risk factors, robustness of findings in multiple sensitivity models, the use of an incident user design to avoid the biases of prevalent user design, and the examination of both the allopurinol exposure and the duration of allopurinol use.

Conclusions

In conclusion, this study shows the cardioprotective effect of allopurinol in preventing MI in the elderly, and shows that this protective effect is evident after 6 months of allopurinol use and is more pronounced after 2 years of allopurinol use. The greatest reductions in the hazard of MI with allopurinol exposure were noted in age groups 65–74 and ≥85 years, females, and Black race. We used an incident user design and the associations noted were robust in multiple sensitivity analyses. These findings are generalizable to all US elderly people aged 65 years and older. Future studies need to examine the potential mechanisms of this cardioprotective effect of allopurinol use, which may uncover pathways either through urate reduction and/or other independent effects of allopurinol [57].

Abbreviations

ACE:

Angiotensin-converting enzyme

CAD:

Coronary artery disease

CI:

confidence interval

HR:

Hazard ratio

ICD-9-CM:

International Classification of Diseases, ninth revision, common modification

MI:

Myocardial infarction

PVD:

Peripheral vascular disease

References

  1. Centers for Disease Control and Prevention. Heart disease. http://www.cdc.gov/heartdisease/facts.htm. Accessed 14 Sept 2016.

  2. Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, Ezzati M, Shibuya K, Salomon JA, Abdalla S, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2197–223.

    Article  PubMed  Google Scholar 

  3. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385(9963):117–71.

    Article  Google Scholar 

  4. Roger VL. Epidemiology of myocardial infarction. Med Clin North Am. 2007;91(4):537–52. ix.

  5. Singh JA, Lu X, Ibrahim S, Cram P. Trends in and disparities for acute myocardial infarction: an analysis of Medicare claims data from 1992 to 2010. BMC Med. 2014;12(1):190.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Sarawate CA, Brewer KK, Yang W, Patel PA, Schumacher HR, Saag KG, Bakst AW. Gout medication treatment patterns and adherence to standards of care from a managed care perspective. Mayo Clin Proc. 2006;81(7):925–34.

    Article  PubMed  Google Scholar 

  7. Singh JA, Hodges JS, Asch SM. Opportunities for improving medication use and monitoring in gout. Ann Rheum Dis. 2009;68(8):1265–70.

    CAS  Article  PubMed  Google Scholar 

  8. Bayram D, Tugrul Sezer M, Inal S, Altuntas A, Kidir V, Orhan H. The effects of allopurinol on metabolic acidosis and endothelial functions in chronic kidney disease patients. Clin Exp Nephrol. 2015;19(3):443–9.

    CAS  Article  PubMed  Google Scholar 

  9. Butler R, Morris AD, Belch JJ, Hill A, Struthers AD. Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension. Hypertension. 2000;35(3):746–51.

    CAS  Article  PubMed  Google Scholar 

  10. Doehner W, Schoene N, Rauchhaus M, Leyva-Leon F, Pavitt DV, Reaveley DA, Schuler G, Coats AJ, Anker SD, Hambrecht R. 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(22):2619–24.

    CAS  Article  PubMed  Google Scholar 

  11. Dogan A, Yarlioglues M, Kaya MG, Karadag Z, Dogan S, Ardic I, Dogdu O, Kilinc Y, Zencir C, Akpek M, et al. Effect of long-term and high-dose allopurinol therapy on endothelial function in normotensive diabetic patients. Blood Press. 2011;20(3):182–7.

    CAS  Article  PubMed  Google Scholar 

  12. El Solh AA, Saliba R, Bosinski T, Grant BJ, Berbary E, Miller N. Allopurinol improves endothelial function in sleep apnoea: a randomised controlled study. Eur Respir J. 2006;27(5):997–1002.

    PubMed  Google Scholar 

  13. Noman A, Ang DS, Ogston S, Lang CC, Struthers AD. Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial. Lancet. 2010;375(9732):2161–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Szwejkowski BR, Gandy SJ, Rekhraj S, Houston JG, Lang CC, Morris AD, George J, Struthers AD. Allopurinol reduces left ventricular mass in patients with type 2 diabetes and left ventricular hypertrophy. J Am Coll Cardiol. 2013;62(24):2284–93.

    CAS  Article  PubMed  Google Scholar 

  15. Rekhraj S, Gandy SJ, Szwejkowski BR, Nadir MA, Noman A, Houston JG, Lang CC, George J, Struthers AD. High-dose allopurinol reduces left ventricular mass in patients with ischemic heart disease. J Am Coll Cardiol. 2013;61(9):926–32.

    CAS  Article  PubMed  Google Scholar 

  16. de Abajo FJ, Gil MJ, Rodriguez A, Garcia-Poza P, Alvarez A, Bryant V, Garcia-Rodriguez LA. Allopurinol use and risk of non-fatal acute myocardial infarction. Heart. 2015;101(9):679-85. doi:10.1136/heartjnl-2014-306670. PubMed PMID: 25561685.

  17. Kok VC, Horng JT, Chang WS, Hong YF, Chang TH. Allopurinol therapy in gout patients does not associate with beneficial cardiovascular outcomes: a population-based matched-cohort study. PLoS One. 2014;9(6):e99102.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol. 1992;45(6):613–9.

    CAS  Article  PubMed  Google Scholar 

  19. Lin DY, Wei LJ. The robust inference for the Cox proportional hazards model. J Am Stat Assoc 1989;84(1074–8):1074–78.

    Article  Google Scholar 

  20. Dubreuil M, Zhu Y, Zhang Y, Seeger JD, Lu N, Rho YH, Choi HK. Allopurinol initiation and all-cause mortality in the general population. Ann Rheum Dis. 2015;74(7):1368–72.

    CAS  Article  PubMed  Google Scholar 

  21. Luk AJ, Levin GP, Moore EE, Zhou X-H, Kestenbaum BR, Choi HK. Allopurinol and mortality in hyperuricaemic patients. Rheumatology. 2009;48(7):804–6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Wei L, Fahey T, Struthers AD, MacDonald TM. Association between allopurinol and mortality in heart failure patients: a long-term follow-up study. Int J Clin Pract. 2009;63(9):1327–33.

    CAS  Article  PubMed  Google Scholar 

  23. Thanassoulis G, Brophy JM, Richard H, Pilote L. Gout, allopurinol use, and heart failure outcomes. Arch Intern Med. 2010;170(15):1358–64.

    CAS  Article  PubMed  Google Scholar 

  24. Goicoechea M, de Vinuesa SG, Verdalles U, Ruiz-Caro C, Ampuero J, Rincon A, Arroyo D, Luno J. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol. 2010;5(8):1388–93.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Givertz MM, Anstrom KJ, Redfield MM, Deswal A, Haddad H, Butler J, Tang WHW, Dunlap ME, LeWinter MM, Mann DL, Felker GM, O'Connor CM, Goldsmith SR, Ofili EO, Saltzberg MT, Margulies KB, Cappola TP, Konstam MA, Semigran MJ, McNulty SE, Lee KL, Shah MR, Hernandez AF. Effects of Xanthine Oxidase Inhibition in Hyperuricemic Heart Failure Patients: The Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (EXACT-HF) Study. Circulation 2015;131(20):1763–71.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Mellin V, Isabelle M, Oudot A, Vergely-Vandriesse C, Monteil C, Di Meglio B, Henry JP, Dautreaux B, Rochette L, Thuillez C, et al. Transient reduction in myocardial free oxygen radical levels is involved in the improved cardiac function and structure after long-term allopurinol treatment initiated in established chronic heart failure. Eur Heart J. 2005;26(15):1544–50.

    CAS  Article  PubMed  Google Scholar 

  27. Guan W, Osanai T, Kamada T, Hanada H, Ishizaka H, Onodera H, Iwasa A, Fujita N, Kudo S, Ohkubo T, et al. Effect of allopurinol pretreatment on free radical generation after primary coronary angioplasty for acute myocardial infarction. J Cardiovasc Pharmacol. 2003;41(5):699–705.

    CAS  Article  PubMed  Google Scholar 

  28. Tarkka MR, Vuolle M, Kaukinen S, Holm P, Eloranta J, Kaukinen U, Sisto T, Kataja J. Effect of allopurinol on myocardial oxygen free radical production in coronary bypass surgery. Scand Cardiovasc J. 2000;34(6):593–6.

    CAS  Article  PubMed  Google Scholar 

  29. Vina J, Gimeno A, Sastre J, Desco C, Asensi M, Pallardo FV, Cuesta A, Ferrero JA, Terada LS, Repine JE. Mechanism of free radical production in exhaustive exercise in humans and rats; role of xanthine oxidase and protection by allopurinol. IUBMB Life. 2000;49(6):539–44.

    CAS  Article  PubMed  Google Scholar 

  30. Movahed A, Nair KG, Ashavaid TF, Kumar P. Free radical generation and the role of allopurinol as a cardioprotective agent during coronary artery bypass grafting surgery. Can J Cardiol. 1996;12(2):138–44.

    CAS  PubMed  Google Scholar 

  31. Bando K, Tago M, Teramoto S. Prevention of free radical-induced myocardial injury by allopurinol. Experimental study in cardiac preservation and transplantation. J Thorac Cardiovasc Surg. 1988;95(3):465–73.

    CAS  PubMed  Google Scholar 

  32. Das DK, Engelman RM, Clement R, Otani H, Prasad MR, Rao PS. Role of xanthine oxidase inhibitor as free radical scavenger: a novel mechanism of action of allopurinol and oxypurinol in myocardial salvage. Biochem Biophys Res Commun. 1987;148(1):314–9.

    CAS  Article  PubMed  Google Scholar 

  33. Stull LB, Leppo MK, Szweda L, Gao WD, Marban E. Chronic treatment with allopurinol boosts survival and cardiac contractility in murine postischemic cardiomyopathy. Circ Res. 2004;95(10):1005–11.

    CAS  Article  PubMed  Google Scholar 

  34. Farquharson CA, Butler R, Hill A, Belch JJ, Struthers AD. Allopurinol improves endothelial dysfunction in chronic heart failure. Circulation. 2002;106(2):221–6.

    CAS  Article  PubMed  Google Scholar 

  35. Flynn Jr WJ, Pilati D, Hoover EL. Effect of allopurinol on venous endothelial dysfunction after resuscitated hemorrhagic shock. Int J Surg Investig. 1999;1(1):11–8.

    PubMed  Google Scholar 

  36. George J, Carr E, Davies J, Belch JJ, Struthers A. High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation. 2006;114(23):2508–16.

    CAS  Article  PubMed  Google Scholar 

  37. Higgins P, Walters MR, Murray HM, McArthur K, McConnachie A, Lees KR, Dawson J. Allopurinol reduces brachial and central blood pressure, and carotid intima-media thickness progression after ischaemic stroke and transient ischaemic attack: a randomised controlled trial. Heart. 2014;100(14):1085–92.

    CAS  Article  PubMed  Google Scholar 

  38. Kanbay M, Huddam B, Azak A, Solak Y, Kadioglu GK, Kirbas I, Duranay M, Covic A, Johnson RJ. 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(8):1887–94.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Kao MP, Ang DS, Gandy SJ, Nadir MA, Houston JG, Lang CC, Struthers AD. Allopurinol benefits left ventricular mass and endothelial dysfunction in chronic kidney disease. J Am Soc Nephrol. 2011;22(7):1382–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Melendez-Ramirez G, Perez-Mendez O, Lopez-Osorio C, Kuri-Alfaro J, Espinola-Zavaleta N. Effect of the treatment with allopurinol on the endothelial function in patients with hyperuricemia. Endocr Res. 2012;37(1):1–6.

    CAS  Article  PubMed  Google Scholar 

  41. Ng KP, Stringer SJ, Jesky MD, Yadav P, Athwal R, Dutton M, Ferro CJ, Cockwell P. Allopurinol is an independent determinant of improved arterial stiffness in chronic kidney disease: a cross-sectional study. PLoS One. 2014;9(3):e91961.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Yelken B, Caliskan Y, Gorgulu N, Altun I, Yilmaz A, Yazici H, Oflaz H, Yildiz A. Reduction of uric acid levels with allopurinol treatment improves endothelial function in patients with chronic kidney disease. Clin Nephrol. 2012;77(4):275–82.

    CAS  Article  PubMed  Google Scholar 

  43. Yiginer O, Ozcelik F, Inanc T, Aparci M, Ozmen N, Cingozbay BY, Kardesoglu E, Suleymanoglu S, Sener G, Cebeci BS. Allopurinol improves endothelial function and reduces oxidant-inflammatory enzyme of myeloperoxidase in metabolic syndrome. Clin Res Cardiol. 2008;97(5):334–40.

    CAS  Article  PubMed  Google Scholar 

  44. Kanbay M, Siriopol D, Nistor I, Elcioglu OC, Telci O, Takir M, Johnson RJ, Covic A. Effects of allopurinol on endothelial dysfunction: a meta-analysis. Am J Nephrol. 2014;39(4):348–56.

    CAS  Article  PubMed  Google Scholar 

  45. Rajagopalan S, Meng XP, Ramasamy S, Harrison DG, Galis ZS. Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. J Clin Invest. 1996;98(11):2572–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Beattie CJ, Fulton RL, Higgins P, Padmanabhan S, McCallum L, Walters MR, Dominiczak AF, Touyz RM, Dawson J. Allopurinol initiation and change in blood pressure in older adults with hypertension. Hypertension. 2014;64(5):1102–7.

    CAS  Article  PubMed  Google Scholar 

  47. Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA. 2008;300(8):924–32.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440(7081):237–41.

    CAS  Article  PubMed  Google Scholar 

  49. Pope RM, Tschopp J. The role of interleukin-1 and the inflammasome in gout: implications for therapy. Arthritis Rheum. 2007;56(10):3183–8.

    CAS  Article  PubMed  Google Scholar 

  50. Crisan TO, Cleophas MC, Oosting M, Lemmers H, Toenhake-Dijkstra H, Netea MG, Jansen TL, Joosten LA. Soluble uric acid primes TLR-induced proinflammatory cytokine production by human primary cells via inhibition of IL-1Ra. Ann Rheum Dis. 2015.

  51. He J, Yang Y, Peng DQ. Monosodium urate (MSU) crystals increase gout associated coronary heart disease (CHD) risk through the activation of NLRP3 inflammasome. Int J Cardiol. 2012;160(1):72–3.

    Article  PubMed  Google Scholar 

  52. Goicoechea M, Garcia de Vinuesa S, Verdalles U, Verde E, Macias N, Santos A, Perez de Jose A, Cedeno S, Linares T, Luno J. Allopurinol and progression of CKD and cardiovascular events: long-term follow-up of a randomized clinical trial. Am J Kidney Dis. 2015;65(4):543–9.

    CAS  Article  PubMed  Google Scholar 

  53. Yan RT, Yan AT, Tan M, Chow CM, Fitchett DH, Ervin FL, Cha JY, Langer A, Goodman SG. Canadian Acute Coronary Syndromes Registry I. Age-related differences in the management and outcome of patients with acute coronary syndromes. Am Heart J. 2006;151(2):352–9.

    Article  PubMed  Google Scholar 

  54. Bradley EH, Herrin J, Wang Y, McNamara RL, Webster TR, Magid DJ, Blaney M, Peterson ED, Canto JG, Pollack Jr CV, et al. Racial and ethnic differences in time to acute reperfusion therapy for patients hospitalized with myocardial infarction. JAMA. 2004;292(13):1563–72.

    CAS  Article  PubMed  Google Scholar 

  55. Wunsch H, Guerra C, Barnato AE, Angus DC, Li G, Linde-Zwirble WT. Three-year outcomes for Medicare beneficiaries who survive intensive care. JAMA. 2010;303(9):849–56.

    CAS  Article  PubMed  Google Scholar 

  56. Tseng VL, Yu F, Lum F, Coleman AL. Risk of fractures following cataract surgery in Medicare beneficiaries. JAMA. 2012;308(5):493–501.

    CAS  Article  PubMed  Google Scholar 

  57. Singh JA. When gout goes to the heart: does gout equal a cardiovascular disease risk factor? Ann Rheum Dis. 2015;74(4):631–4.

    CAS  Article  PubMed  Google Scholar 

Download references

Funding

This material is the result of work supported by research funds from UAB Division of Rheumatology and the resources and use of facilities at the Birmingham VA Medical Center.

Authors’ contributions

JAS: study conception and design, development of study protocol, review of statistical analyses, writing the first draft of the manuscript, critical revisions and submission of the manuscript, and approval of the final manuscript version. SY: data programming and quality monitoring, performance of statistical analyses, critical revisions, and approval of the final manuscript version.

Competing interests

JAS has received research grants from Takeda and Savient, and consultant fees from Savient, Takeda, Regeneron, Merz, Bioiberica, Crealta, and Allergan pharmaceuticals, WebMD, UBM LLC, and the American College of Rheumatology. JAS serves as the principal investigator for an investigator-initiated study funded by Horizon pharmaceuticals through a grant to DINORA, Inc., a 501 (c)(3) entity. JAS is a member of the executive of OMERACT, an organization that develops outcome measures in rheumatology and receives arms-length funding from 36 companies; a member of the American College of Rheumatology’s (ACR) Annual Meeting Planning Committee (AMPC); Chair of the ACR Meet-the-Professor, Workshop and Study Group Subcommittee; and a member of the Veterans Affairs Rheumatology Field Advisory Committee. SY has no conflicts to declare. Neither author has any non-financial conflict.

Consent for publication

Both authors have reviewed this manuscript and provide consent for publication.

Ethics approval and consent to participate

The University of Alabama at Birmingham’s Institutional Review Board approved this study and all investigations were conducted in conformity with ethical principles of research. The ethics committee waived the need for informed patient consent for this database study.

Role of the funding agency

The funding agency had no role in designing, interpreting, or making the decision to submit the study. These decisions were made solely by the authors. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government.

Author information

Authors and Affiliations

  1. Medicine Service, Birmingham VA Medical Center, Birmingham, AL, USA

    Jasvinder A. Singh

  2. Department of Medicine at School of Medicine, and Division of Epidemiology at School of Public Health, University of Alabama at Birmingham (UAB), Faculty Office Tower 805B, 510 20th Street S, Birmingham, AL, 35294, USA

    Jasvinder A. Singh & Shaohua Yu

  3. Department of Orthopedic Surgery, Mayo Clinic College of Medicine, Rochester, MN, USA

    Jasvinder A. Singh

Authors
  1. Jasvinder A. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shaohua Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jasvinder A. Singh.

Additional files

Additional file 1:

Sensitivity analysis adjusted for CAD risk factors. Association of potential risk factors with the hazard of incident MI in patients who received allopurinol with no MI within 365 days before the index date of allopurinol use episode. This file shows that when the main model was additionally adjusted for CAD risk factors such as diabetes, hypertension, tobacco use disorder, and hyperlipidemia, instead of the Charlson-Romano index, the relationship of allopurinol use and allopurinol use duration with the risk of MI did not change. (DOCX 21 kb)

Additional file 2:

Sensitivity analysis adjusted for CAD risk factors, CVD and PVD. Association of various risk factors with the hazard of incident MI in patients who received allopurinol with no MI within 365 days before the index date of allopurinol episode. This file shows that when the main model was additionally adjusted for CAD risk factors (diabetes, hypertension, tobacco use disorder, and hyperlipidemia) instead of the Charlson-Romano index and CAD and peripheral vascular disease, the relationship of allopurinol use and allopurinol use duration with the risk of MI did not change. (DOCX 23 kb)

Additional file 3:

Sensitivity analysis adjusted for CAD risk factors, CVD, PVD, aspirin and colchicine use. Association of various risk factors with the hazard of incident MI in patients who received allopurinol with no MI within 365 days before the index date of allopurinol episode. This file shows that when the main model was additionally adjusted for CAD risk factors (diabetes, hypertension, tobacco use disorder, and hyperlipidemia) instead of the Charlson-Romano index, CAD and peripheral vascular disease, and aspirin and colchicine use, the relationship of allopurinol use and allopurinol use duration with the risk of MI did not change. (DOCX 23 kb)

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Singh, J.A., Yu, S. Allopurinol reduces the risk of myocardial infarction (MI) in the elderly: a study of Medicare claims. Arthritis Res Ther 18, 209 (2016). https://doi.org/10.1186/s13075-016-1111-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13075-016-1111-1

Keywords

  • Allopurinol
  • Myocardial infarction
  • MI
  • Risk factor
  • Pharmacoepidemiology
  • Elderly
  • Predictor
  • Coronary artery disease
  • CAD

Arthritis Research & Therapy

ISSN: 1478-6362

Contact us