Clinical study on efficacy of allopurinol in patients with acute coronary syndrome and its functional mechanism

Clinical Study on efficacy of allopurinol in patients with acute coronary syndrome and its functional mechanism Accepted Manuscript Clinical Study on efficacy of allopurinol in patients with acute cor[.]

Clinical Study on efficacy of allopurinol in patients with acute coronary syndrome and

its functional mechanism

Ying Huang, Chunya Zhang, Zhiqing Xu, Jinghua Shen, Xiaogang Zhang, Huanhua

Du, Kanjian Zhang, Daifu Zhang

PII: S1109-9666(16)30319-0

DOI: 10.1016/j.hjc.2017.01.004

Reference: HJC 113

To appear in: Hellenic Journal of Cardiology

Received Date: 14 November 2016

Revised Date: 30 December 2016

Accepted Date: 4 January 2017

Please cite this article as: Huang Y, Zhang C, Xu Z, Shen J, Zhang X, Du H, Zhang K, Zhang D, Clinical Study on efficacy of allopurinol in patients with acute coronary syndrome and its functional mechanism,

Hellenic Journal of Cardiology (2017), doi: 10.1016/j.hjc.2017.01.004.

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Clinical Study on efficacy of allopurinol in patients with acute coronary

syndrome and its functional mechanism

Ying Huang*, Chunya Zhang, Zhiqing Xu, Jinghua Shen, Xiaogang Zhang, Huanhua Du, Kanjian Zhang, Daifu Zhang*

Department of Cardiology Pudong New Area People ’ s Hospital ShangHai 201200 PR China

*Corresponding authors:

Daifu Zhang Email: zep941@163.com, Tel: +86-021-58951990*2326

Ying Huang Email sunllmm2007@126.com, Tel: +86-021-58951990*2326

Address N0 490 Chuanhuan Road,Chuansha Town,Shanghai Pudong New Area,ShangHai

201200 PR China

[Abstract] Objective: To investigate the therapeutic effect of allopurinol treatment on

acute coronary syndrome and to elucidate its possible mechanism Methods: Patients

with acute coronary syndrome (n=100) were recruited as research subjects in our hospital The patients were randomly divided into two groups (allopurinol group, n = 50) and control group, n= 50) These two groups were treated with conventional antiplatelet, anticoagulation and anti-ischemic therapy, while allopurinol was added to allopurinol group based on conventional treatment The biochemical indexes such as serum creatinine, uric acid, BNP, blood glucose and blood lipid were compared between the two groups Indicators of oxidative stress and inflammatory response (MDA, OX-LDL, NO, hs-CRP and TNF-α) as well as cardiovascular events during

2-years follow-up were recorded Results: On admission, there is no difference in

serum creatinine, uric acid, BNP, blood glucose and lipid levels between the two groups (P > 0.05), and after 1 month of treatment, these levels are better in patients in the allopurinol group than the control group (P < 0.05) After treatment on day 14, 1 month, 3 months, 6 months, 1 year and 2 years follow-up, MDA, OX-LDL and hs-CRP, TNF-α in both groups have decreased, however data from the allopurinol group are significantly lower than the control group (P < 0.05) Additionally, compared with control group, allopurinol treatment significantly elevated the level of

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NO (P < 0.05) The total effective rates of allopurinol group are much higher than the control group both in angina pectoris (93.2% and 76% respectively) and ECG (96% and 82% respectively) Patients in allopurinol group (n=40) and control group (n=41) received stent implantation and there is no statistical difference between them The incidence of cardiovascular events during 2-years follow-up in allopurinol group is

10% while it is 30% in the control group Conclusion: Allopurinol has

remarkable effect in the treatment of ACS and can improve the Oxidative Stress and inflammatory reaction indicators of patients The protective mechanism of allopurinol might be achieved by suppressing the secretion and release of inflammatory mediators TNF-α, hs-CRP and OX-LDL, MDA and increasing level of NO

[Keywords] allopurinol; acute coronary syndrome; cardiovascular events; clinical

efficacy

Introduction

With the increasing incidence of acute coronary syndrome (ACS), it has become a serious threat to human health [1] At present, the main treatments for ACS include anticoagulant and antiplatelet drugs, percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) [2-6] Despite certain curative effect, clinical cardiovascular events such as angina pectoris (AP) and myocardial reinfarction are reported [7-9] The focus of this research is to explore other therapy approaches that could further lower the occurrence of cardiovascular events and this article aims to evaluate the effects of the prototypical xanthine oxidase (XO) inhibitor (allopurinol)

in treating ACS and reducing cardiovascular events, as well as illustrate its possible mechanism

Study Overview and Methods

Overview

100 patients (60 males and 40 females) with ACS were screened for the research from June 2013 to June 2014 in Pudong New Area People ’ s Hospital, and they ranged in age from 30 to 70 years with an average of (56.3±5.2) years Patients had (3.6±1.5) seizures within 48 hours of admission, and 30 cases were ST-segment elevation myocardial infarction (STEMI), 42 were non-ST elevation myocardial infarction

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(NSTEMI) and 28 were unstable AP Exclusion criteria were: patients involved in other clinical trials; revascularization surgery within 3 months; hepatic or renal insufficiency; significant reduction in blood cell counts; allergic to allopurinol Participants were randomly divided into two groups of 50 cases (allopurinol group and control group), and there is no significant difference between the 2 groups All the patients signed the informed consents

The study was approved by the ethics committee of Pudong New Area People’s Hospital

Methods

Both groups were given conventional antiplatelet, anticoagulant and anti-ischemia treatments Patients in allopurinol group received additional allopurinol based on conventional treatment, which consists of a large daily dose of allopurinol 600mg during ACS acute phase (within 14 days) and followed by 200 mg daily until the completion of 4-weeks course Allopurinol was provided by Shanghai Sine Wanxiang Pharmaceuticals Co., Ltd and its national medicine permission number is H31020334

Monitored Indicators

The biochemical indicators such as serum creatinine (SCr), uric acid (UA), B-type natriuretic peptide (BNP), blood glucose (GLU) and blood lipid were compared in patients from both groups upon admission and after 1 month treatment Malondialdehyde (MDA), oxidized low-density lipoprotein (OX-LDL), nitric oxide (NO), high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor alpha (TNF-α) in 2 groups were tested before hospitalization, on day 14 and month 1 treatment, and on month 3, 6, 12, 24 follow-up The therapeutic effects on angina pectoris and electrocardiogram (ECG) after 1 month treatment were evaluated The number of stent placements in the 2 groups were compared Patients were followed

up every week for 2 years after discharge to assess cardiovascular events.‐

Evaluation Criteria on Therapeutic Effect

(1) For AP evaluation, the following observations are taken into account : Remarkable effective: AP attack disappeared or nearly disappeared, or reduction in

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frequency ≥ 80% Effective: Improvement on AP symptoms and frequency decreased by 50% - 80% Ineffective: Reduction in frequency of AP ≤ 50% or no decrease on seizures

(2) ECG evaluation: Remarkable effective: ST segment and T wave indicate normality or near normality Effective: Improvement on ST segment depression and negative T wave Ineffective: No change on ST segment depression or negative T wave

Statistical Considerations‐

Data analysis were performed using statistical software SPSS version 20.0 (IBM, City

of New York, USA) Enumeration data were expressed as percentage and compared

by χ2 test, while measurement data were expressed as mean and standard deviation and compared with t-test A significant difference exists if p-value is less than 0.05

Results

Comparison of Biochemical Indicators

Table I indicates that the levels of serum creatinine, uric acid, BNP, blood glucose and blood lipid show no statistically significant difference (P > 0.05) in the allopurinol group compared to the control group on admission but they have greatly improved after 1 month of treatment (P < 0.05)

Table I Comparison of biochemical indicators between 2 groups

Group Time Point SCr

(µmol/L)

UA (µmol/L)

BNP (pg/ml)

GLU (mmol/L)

Blood Lipid (mg/dL)

Control

Group

On admission

162.3±

28.6

583.6±

34.2

224.2±

37.8

5.3±

0.6

182.7± 27.2

1 month treatment

128.5±

17.3

473.2±

45.6

142.4±

26.7

4.8±

0.5

173.3± 21.1

Allopurinol

Group

On admission

163.7±

31.2

584.2±

35.6

225.1±

41.3

5.4±

0.7

183.1± 25.6

1 month treatment

101.6±

15.4*

414.7±

40.8*

102.6±

18.7*

4.1±

0.4*

150.5± 17.4*

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Asterisks indicate a significant difference between allopurinol group and control group after 1 month treatment (P < 0.05)

Comparison of Oxidative Stress Indicators

Figures 1 and 2 demonstrate that on day 14 and 1 month treatment, and month 3, 6, 12,

24 follow-up, there is a reduction on MDA and OX-LDL in patients from control group, but obviously to a lesser extent when compared with the allopurinol group (P < 0.05) As shown in Figure 3, allopurinol treatment significantly elevated the level of

NO, compared with control group (P < 0.05) ‐

‐

Comparison of Inflammatory Reaction Indicators

As shown in figures 4-5, indicators on day 14 and 1 month after treatment and month

3, 6, 12 and 24 follow-up exhibits a declining trend on the level of hs-CRP and TNF-α

in both groups, and data in allopurinol group is obviously lower than the control group (P < 0.05).‐

‐

Comparison of Efficacy on Angina Pectoris

Table II demonstrates that after 1 month treatment, the total effective rate of angina pectoris in allopurinol group is 93.2%, which is significantly better than the control group (76%)

Table II Comparison of efficacy on Angina Pectoris between 2 groups

Group n

Remarkable Effective

Effective Ineffective

Total Effective Rate (%) Allopurinol Group 50 32 16 2 96* Control Group 50 17 21 12 76 Asterisk indicates a significant difference between allopurinol group and control group (P < 0.05)

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Comparison of ECG Effect‐

Table III shows that the total effective rate of ECG in allopurinol group is evidently higher and achieves 96% after 1 month of treatment compared to control group (82%)

Table III Comparison of ECG effect between 2 groups

Group n

Remarkable Effective

Effective Ineffective

Total Effective Rate % Allopurinol Group 50 30 18 2 96* Control Group 50 15 26 9 82 Asterisk indicates a significant difference between allopurinol group and control group (P < 0.05)

Comparison of PCI and Cardiovascular Events

Patients received stent implantation (n=40 in allopurinol group and n=41 in the control group, respectively and no statistical difference was found between the 2 groups Table IV shows that during 2-years follow-up, the incidence of cardiovascular events in control group is 30%, whereas it is only 10% in allopurinol group

Table IV Comparison of cardiovascular events in 2 groups

Group n AP MI CI STCS LT RVS CVD

CVEI (%) Allopurinol

Group

50 1 1 1 0 1 1 0 10*

Control

Group

50 2 3 2 2 2 3 1 30

Discussion

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Plaque disruption and thrombosis play critical roles in the patho-anatomical mechanism of ACS, where oxidative stress injury, endothelial dysfunction and inflammatory reaction are important parts of the development (10, 11) Recent studies show that oxidative stress (OS) is recognized as an independent risk factor for atherosclerosis (AS), and it can promote the occurrence and development of AS by oxygenation of lipoproteins and inducing gene expression of inflammatory mediators Research by Rajendra NS et al (12) concluded that endogenous xanthine oxidase is the major cause of vascular tissue OS as well as vascular dysfunction XO is mostly produced by vascular endothelial cells, it needs molecular oxygen as electron acceptor

to obtain reactive oxygen species (ROS) by cascade reactions and OX-LDL Lipid peroxides such as MDA are generated by lipid peroxidation of ROS with polyunsaturated fatty acids in biomembrane, which can induce a series of harmful responses like apoptosis, endothelial dysfunction and mechanoenergetic uncoupling in heart And uric acid, the major product of XO, increases the oxygen consumption as it

is tri-oxy-purine (13, 14) Endothelial dysfunction is the initial factors resulting in atherosclerosis as well as induces cardiovascular events Decreased endothelium-dependent vasodilatation (EDV) and NO indicate the impairment of vascular endothelial function Numerous studies (15-17) suggest that inflammatory reaction also plays a vital role in the development of coronary atherosclerosis As the initial factor of AS, inflammation can result in regional neutrophil and monocyte infiltration and lipidosis, which is the principal cause of coronary plaque disruption and hemorrhage, thrombosis and ACS hs-CRP is an acute-phase protein of hepatic origin induced by cytokine (such as interleukin-6) after tissue injury or acute and chronic inflammation, and it is positively correlated with the degree of inflammation and injury Since hs-CRP can reflect the inflammatory status accurately and reliably, it is acting as the clinical indicator for therapeutic effect and observation as well as the independent predictor of ACS (18) TNF-α is an important mediator involved in systemic inflammation, which will induce immunoregulation at low level and pathological lesions at high level It has been verified that TNF-α plays a crucial role in the pathogenesis of ACS (19)

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Oxidative stress leads to endothelial dysfunction and inflammatory reaction, while in turn this dysfunction and reaction can aggravate OS injury

Allopurinol is a typical xanthine oxidase inhibitor whose research and application are mostly related to hyperuricemia and chronic gout, however, recent studies demonstrate that it can also be used for the treatment of cardiovascular disease including heart failure and stable coronary heart disease (CHD) Farquharson

et al (20) suggested that allopurinol contributes to inhibit oxidative stress and improve endothelial function efficiently Research by Cappola et al (21)demonstrates that short-term infusion of allopurinol into the coronary circulation can enhance myocardial efficiency in patients with dilated cardiomyopathy (referred for elective coronary angiography) and will not increase the oxygen cost Some scholars (22) argue that allopurinol can improve OS indicators of patients with chronic stable CHD Clozel (23) found that short-term or long-term allopurinol treatment can increase cardiac output and has no impact on blood pressure from animal experiments However, at present there is no report regarding the curative effect of large-dose allopurinol on ACS in the world (24-26)

This research study indicates that after 1 month treatment, the levels of SCr, UA, BNP, GLU and blood lipid are better in patients of the allopurinol group than the control group (P < 0.05) There is a decrease on MDA, OX-LDL, hs-CRP and TNF-α and an increase of NO in patients of both groups, however the levels in the allopurinol group are significantly lower than the control group (P < 0.05) The total effective rates are obviously higher in the allopurinol group than in control group both for angina pectoris (93.2% and 76% respectively) and ECG (96% and 82% respectively) 40 patients in allopurinol group and 41 in control group received stent implantation and there is no significant statistical difference between the 2 groups.‐Data collected during 2-years follow-up shows that the incidence of cardiovascular events in allopurinol group is 10%, which is clearly lower than the control group (30%) The possible mechanism is that allopurinol can inhibit the activity of xanthine oxidase and relieve oxidative stress (27-30) Allopurinol also contributes to prompting activity of nitric oxide synthase and the balance of NO and ROS as well as the reduction on lipid

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peroxidation of oxyradical, which result in the enhancement of vascular endothelial function and the suppression of inflammatory reaction And it can protect cardiac muscle cell and the structure and function of vascular endothelium, and exhibit improvement on myocardial ischemia, myocardial contractile and diastolic function (31-33).In conclusion, allopurinol has remarkable effect in the treatment of ACS and can improve the OS and inflammatory reaction indicators of patients The protective mechanism of allopurinol on ACS might be achieved by suppressing the secretion and release of inflammatory mediators TNF-α, hs-CRP and OX-LDL, MDA and increasing the level of NO

Acknowledgements:

This study was supported by Shanghai Pudong New Area Science and Technology Development Fund Project (Project Number: PKJ2012-Y15)

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