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Efficacy of high dose Allopurinol in reducing left ventricular mass in patients with left ventricular hypertrophy by comparing its efficacy with Febuxostat - a randomized controlled trial.

Byline: Balwant Lal, Adil Iqbal, Nasir Farooq Butt, Fawad Ahmad Randhawa, Rabia Rathore and Tariq Waseem

Abstract

Objective: To determine the efficacy of high-dose allopurinol in reducing left ventricular mass in patients with left ventricular hypertrophy by comparing its efficacy with febuxostat.

Methods: The randomised controlled interventional study was conducted at Mayo Hospital, Lahore, Pakistan, from April to December 2015, comprising patients with left ventricular hypertrophy on echocardiography. They were randomly divided into two equal groups, with Group A receiving allopurinol and Group B receiving febuxostat. Primary endpoint was reduction in left ventricular mass and left ventricular mass index as calculated by echocardiography. Patients were followed at third and sixth month of enrolment to detect regression. Patients were investigated for eosinophil's count, urine for micro albuminuria and renal function tests to monitor side effects of allopurinol. SPSS 20 was used for data analysis.

Results: There were 76 patients divided into two groups of 38(50%) each. Mean reduction in left ventricular mass between baseline and at six months in Group A and Group B was 35.474+-13.54 and 21.921+-3.33 respectively (p=0.0001) while mean reduction in left ventricular mass index between baseline and at six months was 17.26+-4.36 and 17.63+-21.07 respectively (p=0.0001). Greater improvement was observed in Group A.

Conclusion: Allopurinol was found to be more effective than febuxostatin reducing the left ventricular mass and left ventricular hypertrophy independent of blood pressure.

Keywords: Allopurinol, Febuxostat, Left ventricular mass, Left ventricular mass index. (JPMA 68: 1446; 2018)

Introduction

Cardiovascular disease is a leading cause of death globally, resulting in about 30% of the deaths annually.1 Left ventricular hypertrophy (LVH) is a strong predictor of cardiovascular mortality. LVH predates many cardiovascular events such as arrhythmias, diastolic heart failure, left atrial enlargement and atrial fibrillation.2 LVH is a widespread finding even in patients with normal blood pressure. Longitudinal data has validated results of previous cross-sectional studies, indicating that left ventricular mass (LVM) progressively increases over time with progression increases in the presence of risk factors like diabetes mellitus (DM), hypertension (HTN) and obesity.3,4 Early diagnosis and treatment of LVH is important for two reasons; firstly it is a long-recognised adverse prognostic value, and, second, its ability of regression.5

LVH is diagnosed by either of the three diagnostic tools; electrocardiography (ECG), echocardiography or cardiac magnetic resonance imaging (MRI) which is the gold standard. The accuracy of echocardiographic M mode, in detecting LVH by using interventricular septum thickness, posterior wall thickness and end diastolic diameter of left ventricle (LV), is adequate compared to ECG and 2D echocardiographic mode.6 Prevalence of echocardiographic LVH is different in different populations and varies from 20% to 70% based on criteria used and population studied.7 Irrespective of gender, LVH occurs as a result of adverse ventricular remodelling patterns like concentric and eccentric remodelling.8 Concentric LVH is more commonly seen in pressure overload conditions like HTN, while eccentric LVH is more common among the obese and the aging.9

A novel strategy to prevent development of LVH and to halt its progression is of great importance, especially for a large population suffering from chronic co-morbid illnesses like ischaemic heart disease (IHD), DM, HTN, chronic kidney disease (CKD) and obesity. Different pharmacological agents are used for regression of LVH like angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, diuretics, calcium channel blockers and [beta]-blockers. According to a study, ACE inhibitors reduce LV mass by 15%. Lesser reduction was achieved with diuretics (11%), [beta]-blockers (8%), and calcium-channel blockers (8.5%).10 Recent studies have shown that allopurinol also significantly reduces LV mass, by improving vascular endothelial function through its anti-ischaemic effects and by reducing end systolic volume.11 There is strong basic scientific evidence that LVH is the result of myocardial remodelling, myocyte hypertrophy and myocardial fibrosis.12

Reactive oxygen species, such as hydrogen peroxide and superoxide, are produced by xanthene oxidase.13 Drugs like allopurinol and febuxostat inhibit xanthene oxidase to reduce oxidative stress which results in LVH reduction.14 In addition, Dundee et.al has already reported the role of allopurinol in the regression of LVH in CKD and IHD patients.11,15 International data on the role of allopurinol in reducing LV mass both in CKD and in patients with normal renal functions is available but local literature is lacking.11,15 The current study was planned to fill that knowledge gap.

Patients and Methods

The randomised controlled interventional study was conducted at Mayo Hospital, Lahore, Pakistan, from April to December 2015 after approval from the institutional review board. The sample size was calculated by using 95% confidence interval (CI), 90% power of test and by taking expected mean percentage of reduction in LVM with allopurinol as -5.2+-5.8 and with febuxostat as -1.3+-4.48.10 The sample was raised using non-probability purposive sampling. Consent was taken from every patient. Those included were patients of either gender aged 18-65 years with LVH diagnosed on echocardiography using American Society of Echocardiography criteria9 taking conventional treatment for LVH.

Patients having hypersensitivity to allopurinol or febuxostat (on the basis of history), having congenital heart diseases, glomerular filtration rate (GFR) <60 ml/min/kg, already on allopurinol or febuxostat taking for gout and taking other LVH regressing medications other than mentioned in the initial treatment were excluded. The selected subjects were randomly assigned to either the allopurinol Group A or the febuxostat Group B group by using the lottery method. All patients in both groups underwent echocardiography to assess LVM at presentation. In Group A, patients were given 100mg allopurinol along with conventional treatment initially for two weeks. In case of tolerance to allopurinol, it was then titrated up to dose of 600mg. In Group B, patients were given conventional treatment plus febuxostat 40mg. Outcome data was collected via serial direct contact visits with the patients every twelve weeks at an outpatient clinic until February 2016.

All patients were followed up for a median of 7 months (range: 6-9 months) to find out the incidence of cardiac events, renal problems and serum uric acid levels. The primary endpoint was the echocardiographic LVM reduction after treatment. The LVM was measured at baseline (before treatment) and after three and six months of treatment along with eosinophil count, serum uric acid and renal function tests. Data entry and analysis was done using SPSS 20. Quantitative data was presented as mean+-standard deviation (SD). Qualitative data was presented as frequencies and percentages. One-way multivariate analysis of variance (MANOVA) was used to compare the groups regarding LVM and left ventricular mass index (LVMI) at 1st and 3rd visits. Wilks Lambda test was applied to calculate the significance of difference between the groups.

Table-1: Clinical and biochemical characteristics in both groups at baseline and at six months.

###Allopurinol Group A(n=38)###Febuxostat Group B(n=38)

###Baseline###At 6 months###Baseline###At 6 months

Mean age (in years)###58.74+-9.43###57.32+-12.79

Gender###Male: 20###Male: 22

###Female: 18###Female: 16

Height(in Meters)###1.62+-0.04###1.61+-0.05

Weight(in Kg)###67.39+-6.8###67.10+-6.5###67.91+-8.93###67.66+-8.85

Body mass index(Kg/m2)###25.30+-2.40###25.20+-2.30###25.57+-3.12###25.50+-3.20

Serum urea(mg/dl)###34.47+-5.0###29.26+-2.40###33.76+-5.08###29.26+-2.87

Serum creatinine(mg/dl)###0.78+-0.23###0.55+-0.17###0.7+-0.19###0.52+-0.16

Eosinophil count(%)###1.71+-0.86###1.78+-0.87###1.90+-1.12###2+-1.17

Microalbuminuria(mg/day)###20.92+-4.74###23.43+-6.21###18.11+-4.42###21.43+-6.03

Serum uric acid(mg/dl)###5.57+-0.43###5.48+-0.46###5.63+-0.57###5.38+-0.49

Table-2: Descriptive Statistics and Comparison of Left ventricular mass (LVM) and Left ventricular mass index (LVMI) at 1st and 6 months visit in Group A and Group B.

###Visit###Group-A(Allopurinol)(n=38)###Group-B(Febuxostat)(n=38)

###Mean###SD###Mean###SD

Left ventricular mass(LVM)###1st###251.34###63.15###262.61###96.16

###6 months###215.87###57.99###240.62###85.81

###Wilks Lambda Significance###<0.0001

Left ventricular mass index(LVMI)###1st###143.55###31.73###159.29###76.58

###6 months###126.29###27.37###141.66###55.51

###Wilks Lambda Significance###<0.0001

Table-3: Descriptive Statistics and Comparison of mean reduction of Left ventricular mass (LVM) and Left ventricular mass index (LVMI) at baseline and 6 months between both groups.

###Group-A(n=38)###Group-B(n=38)###P value

###Mean###SD###Mean###SD

Reduction in LVM###35.47###5.16###21.99###10.37###0.0001

Reduction in LVMI###17.26###4.36###17.63###21.07###0.0001

Results

There were 76 patients divided into two groups of 38(50%) each. All (100%) patients in both the groups completed the study. The mean age was 58.74+-9.43 years in Group A and 57.32+-12.79 years in Group B. There were 20(53%) males in Group A and 22(58%) in Group B. There were no significant difference between the groups in terms of gender, age, baseline body mass index (BMI) or baseline blood chemical variables (Table-1). Mean reduction in LVM between baseline and at six months in Group A and Group B was 35.474+- 13.54 and 21.921+-3.33 respectively (p=0.0001) while mean reduction in LVMI between baseline and at six months was 17.26+-4.36 and 17.63+- 21.07 respectively (p=0.0001) (Table-2). Greater improvement was observed in Group A (Table-3).

Discussion

Febuxostat and allopurinol are novel non-purine selective inhibitors of xanthine oxidase that has been shown to attenuate the production of reactive oxygen species and reduce the LV mass in patients with LVH. Previous studies suggest that both allopurinol and febuxostat may confer benefits for patients with LVH and hyperuricaemia. However, the current study made a direct comparison between allopurinol and febuxostatin reducing LVM in patients with LVH. It revealed that allopurinol caused reduction in LVM and regression of hypertrophy in patients with LVH. Also, allopurinol caused greater reduction in patients having higher baseline LVM. It provides the first evidence that allopurinol treatment significantly improved cardiac function compared to febuxostat. In addition, the decrease in LVMI from baseline to 6 months in the allopurinol group was indicatively detected as collated to febuxostat group. Mean reduction in serum uric acid level was higher and significant in febuxostat group.

Both groups were similar in terms of having developed no adverse effects. However, allopurinol was more benign even when used at higher doses and for longer duration. Both drugs did not significantly affect urea, creatinine, eosinophil count and albumin in urine. In this study, reduction in LVM was higher compared to previous studies;15 probably it is because of selection of cases with higher baseline LVM at presentation. However, conclusion of study agrees with previous studies of LVH regression in ischaemic heart disease in which allopurinol also caused regression in LVH without altering the blood pressure.15 Other studies, done in animal models, have shown similar results.16,17 Whole work done so far marks allopurinol as a first drug that has shown categorical retrogression of LVH in human beings in many diseases, including IHD, DM, CKD and HTN.

Finally, LVH regression is linked with reduction in cardiovascular morbidity and mortality apart from blood pressure changes,18 supported by the leading Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial, in which patients having HTN and ECG-proven LVH were studied.19,20 The LIFE study concluded that regression in LVH, regardless of reduction in blood pressure, was linked with lowering of all-cause mortality, sudden cardiac death, heart failure, myocardial infarction and cerebrovascular accidents.19,20 Question to be answered is, how allopurinol regresses LVH. Allopurinol inhibits xanthine oxidase system involved in the production of reactive oxygen species, resulting in decrease in tissue oxidative stress,21 and oxidative stress is an intercede of ventricular hypertrophy.22,23 Therefore, theoretically, the diminution in oxidative stress could interpose regression in LVH.

A clinical trial on 60 heart failure patients compared the effects of oxypurinol versus placebo in improving ejection fraction when added to standard therapy. It concluded that inhibition of xanthine oxidase by oxypurinol in heart failure patients improved left ventricle ejection fraction (LVEF) in patients with LVEF less than or equal to 40% after 1 month of treatment.24 The findings in the current study are parallel with the results of the cited trial24 and means that the reduction in reactive oxygen species with allopurinol can have favourable effects on cardiac hypertrophy without the requirement of reducing blood pressure. A study in diabetic patients with LVH checked the effects of allopurinol in the reduction of LVM by using cardiac MRI. Results showed that allopurinol did a significant reduction in absolute LVM and LVMI.25 The study concluded that allopurinol caused significant reduction in LVM in patients having LVH. These findings are similar to the results of the current study.

Rekraj et al. studied the effect of high-dose allopurinol on LVH and endothelial function in patients with chronic stable angina. Results showed that LVM and LVMI decreased in the allopurinol group compared to the group on placebo, showing a momentous difference. They also suggested that allopurinol not only caused improvement in endothelial function, but also less vascular remodelling.15 All the above-mentioned studies provide strong logical basis regarding the role of allopurinol as an antioxidant. Allopurinol 600 mg/day was used in this study because of its dose-response relationship. Many studies used allopurinol in higher dose of 300 mg/day.11 One study showed achievement of additional 52% improvement in endothelial function when allopurinol was used 600 mg/day.21 Allopurinol was well tolerated in the current study in the dose of 600 mg/day. The maximum dose of allopurinol is up to 900 mg/day.26

Reassuringly, the current study also found that long-term use of allopurinol in high dose had no adverse effect on renal function. In terms of limitations, the current study was conducted at a single centre with a small sample size. Besides, the efficacy of allopurinol was determined with conventional treatment and echocardiography was used instead of cardiac MRI which is more sensitive. Further multi-centred trials are warranted to endorse the results of the current study.

Conclusion

Allopurinol was found to be more effective than febuxostatin reducing the LVM, and may improve cardiac function in LVH patients, at least in part due to reductions in oxidative stress and improvements in endothelial dysfunction, resulting in better end diastolic dysfunction. Moreover, allopurinol was well tolerated by patients even at higher doses used in the study.

Disclaimer: The manuscript was part of a Master's degree thesis in Medicine. Due to non-availability of a registration office for Randomized Control Trials in Pakistan, this study, a RCT, could not obtain a Trial Number and had only an approval from the Institution's Ethical Review Board.

Conflict of Interest: None.

Source of Funding: None.

References

1. Santulli G. Epidemiology of cardiovascular disease in the 21st century: updated numbers and updated facts. J Cardiovasc Dis Res 2013; 1: 1-2.

2. Artham SM, Lavie CJ, Milani RV, Patel DA, Verma A, Ventura HO. Clinical impact of left ventricular hypertrophy and implications for regression. Prog Cardiovasc Dis 2009; 52:153-67.

3. Lieb W, Xanthakis V, Sullivan LM, Aragam J, Pencina MJ, Larson MG, et al. Longitudinal tracking of left ventricular mass over the adult life course: clinical correlates of short-and long-term change in the Framingham offspring study. Circulation 2009; 119: 3085-92.

4. Cheng S, Fernandes VR, Bluemke DA, McClelland RL, Kronmal RA, Lima JA. Age-related left ventricular remodeling and associated risk for cardiovascular outcomes: The Multi-Ethnic Study of Atherosclerosis. Circ Cardiovasc Imaging 2009; 2: 191-8.

5. Pierdoenico SD, Cuccurullo F. Risk reduction after regression of echocardiographic left ventricular hypertrophy in hypertension: a meta-analysis. Am J Hypertens 2010; 23: 876-81.

6. Dubey TN, Paithankar U, Yadav BS. Correlation of echocardiographic left ventricular mass index and electrocardiographic left ventricular hypertrophy variables. Int J Contemp Med Res 2016; 3: 1287-9.

7. Jain A, McClelland RL, Polak JF, Shea S, Burke GL, Bild DE, et al. Cardiovascular imaging for assessing cardiovascular risk in asymptomatic men versus women: the Multi-Ethnic Study of Atherosclerosis(MESA). Circ Cardiovasc Imaging 2011; 4: 8-15.

8. Garg S, de Lemos JA, Ayers C, Khouri MG, Pandey A, Berry JD, et al. Association of a 4-Tiered Classification of LV Hypertrophy With Adverse CV Outcomes in the General Population. JACC Cardiovasc Imaging 2015; 8: 1034-41.

9. Alexescu TG, Cozma A, Sitar-Taut A, Negrean V, Handru MI, Motocu M, et al. Cardiac Changes in Overweight and Obese Patients. Rom J Intern Med 2016; 54: 161-72.

10. Lorell BH, Carabello BA. Left Ventricular Hypertrophy: Pathogenesis, Detection, and Prognosis. Circulation 2000; 102: 470-9.

11. Kao MP, Ang DS, Gandy SJ, Nadir MA, Houston JG, Lang CC, et al. Allopurinol benefits left ventricular mass and endothelial dysfunction in chronic kidney disease. J Am Soc Nephrol 2011; 22: 1382-9.

12. Takimoto E, Kass DA. Role of oxidative stress in cardiac hypertrophy and remodelling. Hypertension 2007; 49: 241-8.

13. Kelley EE, Khoo NK, Hundley NJ, Malik UZ, Freeman BA, Tarpey MM. Hydrogen peroxide is the major oxidant product of xanthine oxidase. Free Radic Biol Med 2010; 48: 493-8.

14. Xu X, Hu X, Lu Z, Zhang P, Zhao L, Wessale JL, et al. Xanthine oxidase inhibition with febuxostat attenuates systolic overload-induced left ventricular hypertrophy and dysfunction in mice. J Card Fail 2008; 14: 746-53.

15. Rekhraj S, Gandy SJ, Szwejkowski BR, Nadir MA, Noman A, Houston JG, et al. High-dose allopurinol reduces left ventricular mass in patients with ischemic heart disease. J Am Coll Cardiol 2013; 61: 926-32.

16. Sagor MA, Tabassum N, Potol MA, Alam MA. Xanthine Oxidase Inhibitor, Allopurinol, Prevented Oxidative Stress, Fibrosis, and Myocardial Damage in Isoproterenol Induced Aged Rats. Oxid Med Cell Longev 2015; 2015: 478039.

17. Xu X, Zhao L, Hu X, Zhang P, Wessale J, Bache R, et al. Delayed treatment effects of xanthine oxidase inhibition on systolic overload-induced left ventricular hypertrophy and dysfunction. Nucleosides Nucleotides Nucleic Acids 2010; 29: 306-13.

18. Schillaci G. Pharmacogenomics of left ventricular hypertrophy reversal: beyond the "one size fits all" approach to antihypertensive therapy. J Hypertens 2004; 22: 2273-5.

19. Lindholm LH, Ibsen H, Dahlof B, Devereux RB, Beevers G, de Faire U, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 2002; 359: 1004-10.

20. Bang CN, Devereux RB, Okin PM. Regression of electrocardiographic left ventricular hypertrophy or strain is associated with lower incidence of cardiovascular morbidity and mortality in hypertensive patient's independent of blood pressure reduction - A LIFE review. J Electrocardiol 2014; 47: 630-5.

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

22. Takimoto E, Kass DA. Role of oxidative stress in cardiac hypertrophy and remodelling. Hypertension 2007; 49: 241-8.

23. Sawyer DB, Siwik DA, Xiao L, Pimentel DR, Singh K, Colucci WS. Role of oxidative stress in myocardial hypertrophy and failure. J Mol Cell Cardiol 2002; 34: 379-88.

24. Cingolani HE, Plastino JA, Escudero EM, Mangal B, Brown J, Perez NG. The effect of xanthine oxidase inhibition upon ejection fraction in heart failure patients: La Plata Study. J Card Fail 2006; 12: 491-8.

25. Szwejkowski BR, Gandy SJ, Rekhraj S, Houston JG, Lang CC, Morris AD, et al. Allopurinol reduces left ventricular mass in patients with type 2 diabetes and left ventricular hypertrophy. J Am Coll Cardiol 2013; 62: 2284-93.

26. Hmar RC, Kannangara DR, Ramasamy SN, Baysari MT, Williams KM, Day RO. Understanding and improving the use of allopurinol in a teaching hospital. Intern Med J 2015; 45: 383-90.
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Publication:Journal of Pakistan Medical Association
Geographic Code:9PAKI
Date:Oct 31, 2018
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