The prognostic impact of allopurinol in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention

doi:10.1016/j.ijcard.2009.08.037

International Journal of Cardiology

Volume 145, Issue 2, 19 November 2010, Pages 257-258

https://doi.org/10.1016/j.ijcard.2009.08.037 Get rights and content

Abstract

Oxidative stress has been shown to increase after acute myocardial infarction and during coronary reperfusion. Allopurinol inhibits xanthine oxidase, an enzyme involved in reperfusion injury. In this study, 40 patients with ST elevation myocardial infarction and symptoms' onset 3–12 h, who underwent primary coronary intervention, were administered either allopurinol (loading dose 400 mg followed by 100 mg for 1 month — group A, 21 patients), or placebo (group B). Allopurinol resulted in a more effective ST-E recovery (P < 0.05 for all comparisons) and lower peak values of troponin I (P = 0.04), CPK (P = 0.01) and CK-MB (P = 0.03). After 1-month follow-up period, 13% lower incidence of major adverse cardiac events (P = 0.002) was also observed in group A, whereas no significant differences in the EF were detected between the groups studied. In our study population, allopurinol administration was beneficial concerning tissue reperfusion, myocardial injury and clinical outcomes.

Introduction

Primary percutaneous coronary intervention (PCI), when available, is the reperfusion strategy of choice for patients with ST segment elevation myocardial infarction (STEMI). Resolution of ST segment elevation (ST-E recovery) after reperfusion therapy is widely used to assess myocardial reperfusion electrocardiographically.

Evidence suggests that reactive oxygen species (ROS) are implicated in the pathogenesis of various pathological states, including myocardial ischemia and reperfusion [1]. One of the enzymes involved in ROS generation is xanthine dehydrogenase, which during reperfusion acts in reverse as xanthine oxidase (free radical-generating enzyme), as a result of the sudden higher availability of oxygen [2]. Allopurinol, alternatively to several myocardial antioxidants which reduce the amount of free radicals after their generation [3], acts as a xanthine oxidase inhibitor. Allopurinol administration has been studied in various species and humans, and has been shown to exhibit a protective effect against ischemia–reperfusion injury, reduction in the infarction size [4], ventricular function improvement [5], lower incidence of arrhythmias [6], and decreased release of myocardial creatine kinase [7].

In the present study the effect of oral administration of allopurinol on the cardiac biomarkers, ST-E recovery, and clinical outcomes in patients with STEMI undergoing primary PCI was addressed.

Section snippets

Methods and Results

Forty patients admitted with STEMI and symptoms' onset between 3 and 12 h were enrolled from June 2005 to June 2006. All patients received standard pharmaceutical treatment according to the current guidelines [8]. On top of the usual care, patients were randomly assigned either to allopurinol (at a loading dose of 400 mg administered immediately after STEMI diagnosis and followed by a maintenance dose of 100 mg for 1 month) (group A, 21 patients), or to placebo (group B, 19 patients). Standard

Discussion

In this study, allopurinol has been administered to patients who underwent PCI at least 3 h after the onset of symptoms, which is probably traduced to a heavier oxidative stress status. Therefore, a more intense scheme of allopurinol administration was adopted, with allopurinol being given less than 45 min before PCI, a considerably shorter time interval compared to previous studies [9]. A daily maintenance dose was also introduced targeting to long-lastingly suppress the endothelial dysfunction

Acknowledgments

The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [12].

References (12)

E.D. Grech et al.
Evidence for free radical generation after primary percutaneous transluminal coronary angioplasty recanalization in acute myocardial infarction
Am J Cardiol
(1996)
D.E. Chambers et al.
Xanthine oxidase as a source of free radical damage in myocardial ischemia
J Mol Cell Cardiol
(1985)
J.R. Stewart et al.
Prevention of free radical-induced myocardial reperfusion injury with allopurinol
J Thorac Cardiovasc Surg
(1985)
E.M. Antman et al.
ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction; a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines
JACC
(2004)
J.G. Coghlan et al.
Allopurinol pretreatment improves postoperative recovery and reduces lipid peroxidation in patients undergoing coronary artery bypass grafting
J Thorac Cardiovasc Surg
(1994)
S. Valente et al.
Predictors of in-hospital mortality after percutaneous coronary intervention for cardiogenic shock
Int J Cardiol
(2007)

There are more references available in the full text version of this article.

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Letter to the EditorThe prognostic impact of allopurinol in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention

Abstract

Introduction

Section snippets

Methods and Results

Discussion

Acknowledgments

Am J Cardiol

J Mol Cell Cardiol

J Thorac Cardiovasc Surg

JACC

J Thorac Cardiovasc Surg

Int J Cardiol

Letter to the Editor
The prognostic impact of allopurinol in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention