LITHUANIAN UNIVERISTY OF HEALTH SCIENCES FACULTY OF MEDICINE Department of Rheumatology THE EFFECT OF URATE LOWERING THERAPY ON CARDIOVASCULAR DISEASE IN NON-GOUT INDIVIDUALS

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LITHUANIAN UNIVERISTY OF HEALTH SCIENCES

FACULTY OF MEDICINE

Department of Rheumatology

THE EFFECT OF URATE LOWERING THERAPY ON

CARDIOVASCULAR DISEASE IN NON-GOUT INDIVIDUALS

Author: Tesseley Thomas

Supervisor: Dr Eleonora Norkuvienė

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1. SUMMARY

Author: Tesseley Thomas

Scientific Supervisor: Dr Eleonora Norkuvienė

Research title: The effect of urate lowering therapy on cardiovascular disease in non-gout individuals.

Aim: To review the effect of urate lowering therapy to improve cardiovascular outcomes in individuals with asymptomatic hyperuricemia and in patients with known cardiovascular diseases with or without hyperuricemia.

Objectives

1. To review the role of urate lowering therapy on cardiovascular outcomes in individuals with asymptomatic hyperuricemia without cardiovascular disease

2. To review the role of urate lowering therapy on cardiovascular outcomes in non-gout patients with known cardiovascular diseases with or without hyperuricemia

3. To prepare a practical recommendation on the role of urate lowering therapy to improve cardiovascular outcomes in non-gout patients

Methodology

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4 Results

Out of the 26 studies with the aim to evaluate the cardiovascular outcomes on urate lowering therapy, 10 were related to people with asymptomatic hyperuricemia and 16 were related to patients with established cardiovascular disease with or without hyperuricemia: 4 coronary artery disease, 8 chronic heart failure, 2 myocardial infarctions and 2 ischemic stroke. Overall, thirteen studies reported significant decrease in cardiovascular disease mortality, all-cause mortality and cardiovascular events such as myocardial infarction or stroke. Four studies discovered

improvement in endothelial function and vascular oxidative stress. Interestingly, three studies showed a decrease in left ventricle mass and another two showed improvements in carotid intima-media thickness, time to ST depression, total exercise time and time to angina onset. However, four studies failed to show any association between urate lowering therapy and cardiovascular outcome.

Conclusions

1. Xanthine oxidase inhibitors could exert a preventive effect on the incidence of major cardiovascular events and mortality in patients with asymptomatic hyperuricemia. 2. There is a possible direct relationship between allopurinol and improved cardiovascular

outcomes in patients with established cardiovascular disease. However, more large-scale studies need to be done to clarify the underlying mechanisms and assess the risk-benefit ratio of allopurinol use.

3. High dose allopurinol use, defined as ≥300 mg, is associated with a lower risk of

cardiovascular events than low dose allopurinol use, suggesting that higher doses may be more beneficial to reduce cardiovascular disease.

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5 Practical recommendations

1. All individuals diagnosed with hyperuricemia should be made aware of its association with cardiovascular disease

2. Prescribing allopurinol may be an improved treatment strategy to prevent the

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2. ACKNOWLEDGEMENTS

I would like to express my sincere gratitude to Dr Eleonora Norkuvienė for her guidance and support throughout this research.

3. CONFLICTS OF INTEREST

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4. ABBREVIATIONS

1. CVD- Cardiovascular disease 2. CAD- Coronary artery disease 3. HF- Heart failure

4. UA- Uric acid

5. ULT- Urate lowering therapy 6. CV- Cardiovascular

7. URAT1- Urate transporter 1 8. XO- Xanthine oxidase

9. ROS- Reactive oxygen species 11. OS- Oxidative stress

12. CHF- Chronic heart failure 13. CRP- C-reactive protein

15. TNF-α- Tumour necrosis factor-alpha 16. CHD- Coronary heart disease

17. XOI- Xanthine oxidase inhibitors 18. LVH- Left ventricle hypertrophy 19. LVM- Left ventricle mass

20. RCT- Randomized controlled trial 21. LVEF- Left ventricle ejection fraction 23. MI- Myocardial infarction

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5. INTRODUCTION

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally [1]. According to epidemiological data, each year CVD causes approximately 3.9 million deaths in Europe and over 1.8 million deaths in the European Union [2]. Among CVD, coronary artery disease (CAD) is the primary cause of death in developed countries [3], with other common causes including heart failure (HF) and stroke [4].

The worldwide prevalence of hyperuricemia has also significantly increased in recent decades. The progressive increase in serum uric acid (UA) levels may be linked to rising overweight and obesity in the population, as well as the increase in consumption of

sugar-sweetened beverages, foods rich in purines, and alcohol. Hyperuricemia is well established to be a risk for developing gout, and now there is substantial evidence supporting the close

relationship between serum UA and risk of CVD: including CAD, new-onset HF and stroke [6]. There are several possible mechanisms underlying this association such as oxidative stress (OS) and endothelial dysfunction. Therefore, careful management of hyperuricemia is crucial to prevent or treat those systemic diseases but despite this, hyperuricemia often remains untreated. Studies have shown how urate lowering therapy (ULT) in gout is beneficial to reducing risk of cardiac events but none has yet supported recommending pharmacological treatments for

asymptomatic hyperuricemia [5]. Using ULT can test the hypothesis that reduction of serum UA could prevent or treat CVD. If ULT decreases the development of CVD, the global burden of the disease would be prominently reduced [7].

The few reporting of positive outcomes, that explored the possibility of using ULT to attenuate the development of CVD, had prompted calls for large-scale clinical trials but

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6. AIMS AND OBJECTIVES

Aim:

To review the effect of urate lowering therapy to improve cardiovascular outcomes in individuals with asymptomatic hyperuricemia and in patients with known cardiovascular diseases with or without hyperuricemia.

Objectives

1. To review the role of urate lowering therapy on cardiovascular outcomes in individuals with asymptomatic hyperuricemia without cardiovascular disease

2. To review the role of urate lowering therapy on cardiovascular outcomes in non-gout patients with known cardiovascular diseases with or without hyperuricemia

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7. LITERATURE REVIEW

Hyperuricemia in cardiovascular disease

It was reported that the overall risk of CVD mortality increased by 15% for each increase of 1 mg/dL of UA [15]. To consider using ULT to improve CVD outcomes in patients, it is important to be aware of the several plausible pathogenetic mechanisms which have been proposed in literature to explain the underlying association between hyperuricemia and CVD.

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11 Besides XO activity, a number of studies have also demonstrated that UA itself is

independently associated with the concentration of pro-inflammatory mediators such as C-reactive protein (CRP), interleukin-6 and tumour necrosis factor-alpha (TNF-α) [17].

Inflammation is considered to be a key factor in the development of CAD. Additionally, UA is regarded to have a role in heart failure by stimulating mitogen activated protein kinases, platelet derived growth factor and cyclooxygenase-2 [51].

Several studies have shown evidence to the relationship between serum UA and lipid profiles. There is a positive correlation for serum UA with triglycerides, total cholesterol and LDL levels, and an inverse relationship for serum UA with HDL. HDL is a known protective factor for CVD risk [56]. The presence of both dyslipidaemia and hyperuricemia doubles the CVD risk as seen by the rise in levels of CVD markers such as CRP, ApoA1, ApoB and Lipoprotein (a) in such cases [57].

In summary, hyperuricemia negatively affects vascular function by playing a significant role in the development of OS [19]. By decreasing NO bioavailability, hyperuricemia induces inflammation and endothelial dysfunction, which may promote CVD [16].

Xanthine oxidase inhibitors

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12 inhibiting ROS formation during XO activity [52]. There are also several studies showing XO inhibition improves endothelial dysfunction and reduces circulation markers of OS in CHF patients, giving evidence to the theory of how XO inhibition reduces oxidant generation [51].

Fig. 1. Schematic representation of uric acid formation and elimination showing the drugs

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8. METHODS

Literature was identified by searching PubMed with the combination of the following search terms: ‘urate lowering therapy’ ‘urate lowering treatment’, ‘allopurinol’, ‘febuxostat’, ‘xanthine oxidase inhibitor’, ‘hyperuricemia’ ‘cardiovascular disease’, ‘cardiovascular risk’, ‘coronary artery disease’, ‘chronic heart failure’, ‘myocardial infarction’ and ‘stroke’ (table 1). Further, filters were applied (table 2). The final resulting papers were included or excluded based on reading the title and abstract and articles eligibility was assessed according to the PICO criteria (table 3, 4). This literature review studies the role of ULT in hyperuricemia and in four CVDs namely CAD, CHF, myocardial infarction (MI) and stroke. Each disease was analysed on the correlation between ULT and disease outcome.

Table 1. List of terms used in the initial search Searched terms

- Urate lowering therapy/ treatment - Allopurinol

- Febuxostat

- Xanthine oxidase inhibitor - Hyperuricemia

- Cardiovascular disease - Cardiovascular risk - Coronary artery disease - Chronic heart failure - Myocardial infarction - Stroke

Table 2. Filters that were applied after the initial search Filters

Date range: Within ten years (last search was performed 10th February 2020) Species: Human

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Table 3. PICO criteria for inclusion

P I C O

Population Intervention Comparison Outcome

Individuals with asymptomatic hyperuricemia and/or known CVDs: CAD, CHF, MI, ischemic stroke

ULT All selected

studies were compared to a control group or an alternate ULT Effectiveness in improving cardiac outcomes: CVD mortality, all-cause mortality, CV events such as MI or stroke, endothelial function, vascular OS, left ventricle mass (LVM), carotid intima-media thickness (CIMT), time to ST depression, total exercise time, time to angina onset

Table 4. PICO criteria for exclusion

P I C O

Population Intervention Comparison Outcome

Patients with gout or patients on

haemodialysis

Any medications other than ULT

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15 Study selection

The review of selected studies was performed following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow chart guidelines. Records identified from the initial search was 2025 before filters were applied. After records were screened of the remaining 493 articles, 467 were excluded due reasons presented on Figure 2 [62]. A total of 26 full text articles were assessed as eligible and included in the review.

Identification

Screening

Eligibility

Inclusion

Fig 2. Adapted PRISMA flow chat [62]. n: Sample size; ULT: urate lowering therapy; CVD: cardiovascular disease

Records identified through database searching

n=2025

Records excluded (n=467) • Abstracts only with no external link (n=186) • Systematic reviews (n=24) • Metanalysis (n=4) • Literature reviews (n=43) • Gout (n=35)

• Studies assessing only renal end points/ haemodialysis patients (n=24) • Non-ULT medications (n=11) • Not specific to hyperuricemia and/or CVD (n=140)

Records screened after filter application

n=493

Total studies reviewed: n=26

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16 Quality and risk of bias assessment

Studies were reviewed thoroughly to assess quality based on The Cochrane

recommendations for systematic reviews of interventions by Higgins [63] and this is presented on table 5. All possible risk of bias is classified into: low risk of bias (+), unclear risk of bias (?) or high risk of bias (-) and a total score out of six is given. Results show that fifteen studies have low risk of bias for all key domains [25, 27, 28, 33, 58, 61, 36, 60, 37, 39, 41, 42, 43, 48, 45] and many studies have unknown risk of bias for one or more key domains.

Table 5. Quality risk of bias assessment

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17 Goicoechea et al. [40] + - - + + + 4 Larsen et al. [41] + + + + + + 6 Singh et al. [42] + + ? + + + 5 Singh et al. [43] + + + + + + 6 Kojima et al [48] + + ? + + + 5 Ramirez et al. [44] ? ? ? + + + 3 Kambay et al. [45] + + + + + + 6

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9. RESULTS

Out of the 26 studies on ULT, 10 were related to people with asymptomatic hyperuricemia and 16 were related to patients with established CVD with or without hyperuricemia: 4 CAD, 8 CHF, 2 MI and 2 ischemic stroke. Overall, thirteen studies reported significant decrease in CVD mortality, all-cause mortality and CV events such as MI or stroke. Four studies discovered improvement in endothelial function and vascular OS. Interestingly, three studies showed a decrease in LVM and another two showed improvements in CIMT, time to ST depression, total exercise time and time to angina onset. However, four studies failed to show any association between ULT and CV outcome.

Studies of association between ULT and coronary artery disease

In CAD, a potentially reversible factor leading to cardiac death is left ventricular

hypertrophy (LVH) and it is assessed by measurement of LVM [23]. In a cross-sectional study with 96 control group patients on anti-ischemic drug treatment and another 96 patients that additionally took allopurinol minimum dose 100 mg, it was reported that Allopurinol treatment was associated with a significant decrease in LVM as well as better glycaemic control when compared with control patients. Alem et al. [24] concluded these positive findings should encourage more research on the extended effects of allopurinol. Similarly, Rekraj et al. [25] in a small, randomized, double-blind, placebo controlled study with 66 patients diagnosed with CAD and LVH proved a reduction in LVM and left ventricle end-systolic volume with 300 mg

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19 this study documented an increase in total exercise time, time to onset of angina and time to ECG ST‐segment depression.

Studies of association between ULT and chronic heart failure

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20 Xiao at al. [59] found allopurinol group given 300 mg had improved left ventricle function and therefore better CV outcomes compared to the control group and allopurinol was reported to be safe and effective for these patients.

Studies of association between ULT and myocardial infarction

Huang et al. [34] investigated 100 patients with acute coronary syndrome, randomly divided into two groups of 50 patients, an allopurinol group and a control group. Allopurinol 600 mg was given during the acute phase within 14 days, then 200 mg till 4 weeks. Compared to the control group, there was an improvement in levels of biochemical markers such as serum creatinine, UA, brain natriuretic peptide, blood lipid and blood glucose. Whilst levels of NO increased, indicators of OS and inflammatory response such as malondialdehyde, oxidized LDL, high sensitivity CRP and TNF-α decreased after the treatment period, thus proving the protective mechanism of allopurinol. The incidence of CV events during 2 years of follow-up was 10% and 30% in the allopurinol group and control group respectively. Moreover, a case-control study also associated allopurinol with a reduced risk of MI after comparing patients with first-ever MI and matched controls [35].

Studies of association between ULT and ischaemic stroke

A randomised, double-blind, placebo-controlled study examined the effect of 1-year treatment with allopurinol 300 mg on 80 patients with recent stroke. Both measured surrogate markers of CV risk, central blood pressure and CIMT, were lower compared with placebo [36]. Another RCT evaluating 70 patients after stroke found functional status to be significantly improved with allopurinol 200 mg 3 months when compared to the control group [60].

Studies of association between ULT and asymptomatic hyperuricemia

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21 for 100 mg group, 69.7 for the 200 mg group and 47.6 for the ≥300 mg group. Compared with low-dose users, high-dose users had significant reductions in the risk and mortality and this is further suggestive of a dose-response relationship with CV events. A retrospective case-matched cohort study reported hyperuricemic patients treated with ULT had a lower risk of all-cause death relative to patients who did not receive ULT [39]. Goicoechea et al. [40] found long-term treatment with allopurinol 100 mg given for 2 years reduced cases of incident MI. However, another study conducted with the same low dosage of ULT given for more than 1 year was unable to demonstrate any link. Possible explanations may include that allopurinol doses higher than those used in this study are required to achieve CV risk reduction or that the CV effect of allopurinol is not mediated through low urate levels [41]. Longer durations of allopurinol use reduced the risk of incident MI and ischemic stroke incrementally in patients above 65 years of age in two retrospective cohort studies. Even though Singh et al. [42] [43] reported no adverse side effects, it was concluded that future studies should further assess the risk-benefit ratio for allopurinol use. One report where 1070 elderly patients with hyperuricemia and CVD risks were treated with febuxostat up to 40 mg or non-febuxostat which included non-treatment or a low dose of allopurinol 100 mg for a period of 36 months. A higher proportion of 90.1% patients in the febuxostat given group achieved serum UA reduction <6 mg/dl, approximately 4.5 mg/dl, and only 28% patients achieved this in the non-febuxostat group and the mean serum UA level in this group was a higher value of 6.76 mg/dl. Evaluated primary end points included all-cause death, stroke, CAD and heart failure. There was no significant difference in CV clinical

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22 Details extracted for each article is summarised and are as follows: name of the author, type of study, population size (n)/ established disease/ hyperuricemia, intervention, outcomes measured, quality score out of total 6, statistical significance and conclusion (table 6).

Table 6. Summary of the effects of ULT on CVD or hyperuricemia

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29 Statistically significant 19 Chen et al. 2015 [39] retrospe ctive case-matche d cohort study 3088 hyperur icemia Benzbromar one, Allopurinol >6years CVD mortality, all-cause mortality 5 HR 0.60 CI 0.41–0.88 (p=0.01) Statistically significant Treatment with ULT had better survival than control group. 20 Goicoec hea et al. 2014 [40] parallel RCT 113 hyperur icemia Allopurinol 100 mg 2 years Incident MI 4 HR, 0.43. 95% CI 0.21-0.88. (p=0.02) Statistically significant Long-term treatment with allopurinol may reduce MI risk. 21 Larsen et al. 2016 [41] case control study 538 hyperur icemia Allopurinol 100 mg >1 year

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31 CAD: coronary artery disease; <: more than; LVM: left ventricle mass; LV: left ventricle; ULT:

urate lowering therapy; CVD: cardiovascular disease; IHD: ischemic heart disease; OS: oxidative stress; RCT: randomized controlled trial; CHF: chronic heart failure; HF: heart failure;

LVEF: left ventricle ejection fraction; QoL: quality of life; MI: myocardial infarction; UA: uric acid; HR: hazard ratio; CI: confidence interval; mRS: modified Rankin scale; BNP: brain

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10. DISCUSSION

All primary and secondary cardiac end points showed a significant improvement in twenty-two out of the twenty-six CVD studies which included decreased rate of CVD mortality, all-cause mortality, LVM, incidence of cardiac events such as MI or stroke and finally

improvement in vascular OS and endothelial dysfunction. No articles were found which evaluated ULT other than XOIs. There were several studies which highlighted the underlying mechanism for the improvement in clinical outcome be due to reduction in vascular OS [26], improvement in endothelial dysfunction and cardiac structure. These mechanisms are note noteworthy because both endothelial function and cardiac function are independent predictors of mortality. Other mechanisms could contribute, such as allopurinol reducing myocardial oxygen consumption for a particular stroke volume, and this has been confirmed in a RCT in patients with chronic stable angina [38]. Four papers also proved this theory by assessing endothelial function by forearm venous plethysmography and vascular OS by intra-arterial co-infusion of vitamin C and acetylcholine. These effects of allopurinol may be valuable for reducing future CV mortality.

Interestingly, three out of all four reports which showed no evidence of improvement in CV outcomes were all studies based on CHF [31,32,33]. This suggests there is a reduced

likelihood that allopurinol would work to improve CHF prognosis as compared to CAD, MI and stroke.

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33 Febuxostat is a less promising non purine-like XOI as the FDA recently issued concern for the CV safety of the drug based on the preliminary results from a large clinical trial based on over 6000 patients [22]. However, this trial reported an increase in CV mortality among gout patients only. From this review of literature, one study in 1070 individuals with hyperuricemia found febuxostat showed no difference in CV outcomes when compared to allopurinol [48] and another showed allopurinol to be more effective in reducing LVM [61]. However, despite the report of another study which found fewer CVD mortality in CHF patients receiving febuxostat compared to allopurinol [20], a conclusion is still difficult to reach on which medication is more effective as sample sizes were limited and the observation period was relatively short. Therefore, more studies need to be done to establish a distinction between the efficacy and safety of

different XOI in CVD.

It is important to acknowledge the potential adverse reactions of ULT when considering XOI beyond the usual indication of gout, including severe allergic reactions and other serious side effects [46, 49, 50]. Even though only one out of the total reviewed literatures reported such cases [20], it is to be noted that the majority of studies included the adult population, and some studies suggest that the side effects of allopurinol or febuxostat could potentially be much more significant in the elderly above the age of 65. Nevertheless, the overall benefit of ULT on survival may outweigh the impact of rare serious adverse effects.

From the results, it is evident that there is a correlation between treatment with ULT and CVD. Allopurinol, plays an important role in preventing CVDs in individuals with

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34 Strengths and limitations

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11. CONCLUSIONS

1. XOIs could exert a preventive effect on the incidence of major CV events and mortality in patients with asymptomatic hyperuricemia.

2. There is a possible direct relationship between allopurinol and improved CV outcomes in patients with established CVD. However, more large-scale studies need to be done to clarify the underlying mechanisms and assess the risk-benefit ratio of allopurinol use. 3. High dose allopurinol use, defined as ≥300 mg, is associated with a lower risk of CV

events than low dose allopurinol use, suggesting that higher doses may be more beneficial to reduce CVD.

4. Febuxostat did not increase the overall risk of adverse CV outcomes among individuals with hyperuricemia when compared to allopurinol but more studies need to be done to assess the efficacy and safety of the drug in CVD.

12. PRACTICAL RECOMMENDATIONS

1. All individuals diagnosed with hyperuricemia should be made aware of its association with CVD

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LITHUANIAN UNIVERISTY OF HEALTH SCIENCES FACULTY OF MEDICINE Department of Rheumatology THE EFFECT OF URATE LOWERING THERAPY ON CARDIOVASCULAR DISEASE IN NON-GOUT INDIVIDUALS