Therapeutic Use of High-Dose Allopurinol in Angina Pectoris
Therapeutic Use of High-Dose Allopurinol in Angina Pectoris
Objectives The aim of this study was to evaluate the effect of high-dose allopurinol on vascular oxidative stress (OS) and endothelial function in subjects with stable coronary artery disease (CAD).
Background Allopurinol, a xanthine oxidase inhibitor, prolongs the time to chest pain during exercise in angina. We sought to ascertain whether allopurinol also improves endothelial dysfunction in optimally treated CAD patients, because such an effect might be of value to reduce future cardiovascular mortality. The mechanism of the anti-ischemic effect of allopurinol could be related to its reducing xanthine oxidase-induced OS, and our second aim was to see whether allopurinol really does reduce vascular tissue OS in CAD patients.
Methods A randomized, double-blind, placebo-controlled, crossover study was conducted in 80 patients with CAD, comparing allopurinol (600 mg/day) with placebo. Endothelial function was assessed by forearm venous occlusion plethysmography, flow-mediated dilation, and pulse wave analysis. Vascular OS was assessed by intra-arterial co-infusion of vitamin C and acetylcholine.
Results Compared with placebo, allopurinol significantly improved endothelium-dependent vasodilation, by both forearm venous occlusion plethysmography (93 ± 67% vs. 145 ± 106%, p = 0.006) and flow-mediated dilation (4.2 ± 1.8% vs. 5.4 ± 1.7%, p < 0.001). Vascular oxidative stress was completely abolished by allopurinol. Central augmentation index improved significantly with allopurinol (2.6 ± 7.0%, p < 0.001) but not with placebo.
Conclusions Our study demonstrates that, in optimally treated CAD patients, high-dose allopurinol profoundly reduces vascular tissue OS and improves 3 different measures of vascular/endothelial dysfunction. The former effect on OS might underpin the anti-ischemic effect of allopurinol in CAD. Both effects (on OS and endothelial dysfunction) increase the likelihood that high-dose allopurinol might reduce future cardiovascular mortality in CAD, over and above existing optimum therapy. (Exploring the therapeutic potential of xanthine oxidase inhibitor allopurinol in angina; ISRCTN15253766)
High-dose allopurinol has recently been shown to markedly prolong the time to chest pain and to ST-segment depression during exercise in patients with chronic stable angina. This might be related to previous experimental work suggesting that allopurinol somehow reduces myocardial oxygen consumption for a given stroke volume. Two key questions naturally arise from this. First, what is the mechanism in man whereby allopurinol delays chest pain during exercise? Second, will this anti-ischemic symptomatic benefit translate into allopurinol also improving survival in angina? Our study was designed to shed light on both of these key questions.
With regard to the first question, work in experimental heart failure shows that the main xanthine oxidase (XO)-related factor that influences myocardial oxygen consumption is oxidative stress (OS). If allopurinol really does reduce XO-induced OS in human angina, then such an effect could well contribute to its anti-chest pain effect. Yet, there are currently no data (in animals or man) on whether allopurinol really does reduce OS in coronary artery disease (CAD). Furthermore, even if it does usually reduce OS, does it still do so in the presence of full contemporary CAD therapy.
With regard to the second question posed, we also sought to gain insight into whether allopurinol might also one day improve survival in CAD. Overall survival is not usually improved in angina by treatments that improve symptoms (e.g., nitrates, amlodipine, angioplasty), aside from beta-blockers. Improved survival in CAD is usually produced instead by drugs that reduce plaque formation and instability by multiple mechanisms, including by reducing endothelial dysfunction (ED) (e.g., statins and angiotensin-converting enzyme [ACE] inhibitors). We therefore sought also to see whether allopurinol improved ED in optimally treated CAD patients to gain insight into whether there is any prospect that allopurinol might also improve survival in CAD.
One particularly relevant issue here is the contemporary treatment that CAD patients nowadays receive. This is because there is a strong possibility that treatments like statins and ACE inhibitors might already have so improved ED that targeting XO to further improve ED could be futile. As an example of this possibility, the negative results of the PEACE (Prevention of Events with Angiotensin Converting Enzyme Inhibition) trial might have been because the ED of patients had been so improved already by statin therapy as to make ACE inhibitors ineffective. Therefore, a novel feature of our study was that we studied only optimally treated CAD patients to see whether XO inhibition can still improve ED and XO-induced OS in the presence of optimal CAD co-treatment. Only if allopurinol gives added value over contemporary treatment is it likely to be of practical therapeutic use.
Abstract and Introduction
Abstract
Objectives The aim of this study was to evaluate the effect of high-dose allopurinol on vascular oxidative stress (OS) and endothelial function in subjects with stable coronary artery disease (CAD).
Background Allopurinol, a xanthine oxidase inhibitor, prolongs the time to chest pain during exercise in angina. We sought to ascertain whether allopurinol also improves endothelial dysfunction in optimally treated CAD patients, because such an effect might be of value to reduce future cardiovascular mortality. The mechanism of the anti-ischemic effect of allopurinol could be related to its reducing xanthine oxidase-induced OS, and our second aim was to see whether allopurinol really does reduce vascular tissue OS in CAD patients.
Methods A randomized, double-blind, placebo-controlled, crossover study was conducted in 80 patients with CAD, comparing allopurinol (600 mg/day) with placebo. Endothelial function was assessed by forearm venous occlusion plethysmography, flow-mediated dilation, and pulse wave analysis. Vascular OS was assessed by intra-arterial co-infusion of vitamin C and acetylcholine.
Results Compared with placebo, allopurinol significantly improved endothelium-dependent vasodilation, by both forearm venous occlusion plethysmography (93 ± 67% vs. 145 ± 106%, p = 0.006) and flow-mediated dilation (4.2 ± 1.8% vs. 5.4 ± 1.7%, p < 0.001). Vascular oxidative stress was completely abolished by allopurinol. Central augmentation index improved significantly with allopurinol (2.6 ± 7.0%, p < 0.001) but not with placebo.
Conclusions Our study demonstrates that, in optimally treated CAD patients, high-dose allopurinol profoundly reduces vascular tissue OS and improves 3 different measures of vascular/endothelial dysfunction. The former effect on OS might underpin the anti-ischemic effect of allopurinol in CAD. Both effects (on OS and endothelial dysfunction) increase the likelihood that high-dose allopurinol might reduce future cardiovascular mortality in CAD, over and above existing optimum therapy. (Exploring the therapeutic potential of xanthine oxidase inhibitor allopurinol in angina; ISRCTN15253766)
Introduction
High-dose allopurinol has recently been shown to markedly prolong the time to chest pain and to ST-segment depression during exercise in patients with chronic stable angina. This might be related to previous experimental work suggesting that allopurinol somehow reduces myocardial oxygen consumption for a given stroke volume. Two key questions naturally arise from this. First, what is the mechanism in man whereby allopurinol delays chest pain during exercise? Second, will this anti-ischemic symptomatic benefit translate into allopurinol also improving survival in angina? Our study was designed to shed light on both of these key questions.
With regard to the first question, work in experimental heart failure shows that the main xanthine oxidase (XO)-related factor that influences myocardial oxygen consumption is oxidative stress (OS). If allopurinol really does reduce XO-induced OS in human angina, then such an effect could well contribute to its anti-chest pain effect. Yet, there are currently no data (in animals or man) on whether allopurinol really does reduce OS in coronary artery disease (CAD). Furthermore, even if it does usually reduce OS, does it still do so in the presence of full contemporary CAD therapy.
With regard to the second question posed, we also sought to gain insight into whether allopurinol might also one day improve survival in CAD. Overall survival is not usually improved in angina by treatments that improve symptoms (e.g., nitrates, amlodipine, angioplasty), aside from beta-blockers. Improved survival in CAD is usually produced instead by drugs that reduce plaque formation and instability by multiple mechanisms, including by reducing endothelial dysfunction (ED) (e.g., statins and angiotensin-converting enzyme [ACE] inhibitors). We therefore sought also to see whether allopurinol improved ED in optimally treated CAD patients to gain insight into whether there is any prospect that allopurinol might also improve survival in CAD.
One particularly relevant issue here is the contemporary treatment that CAD patients nowadays receive. This is because there is a strong possibility that treatments like statins and ACE inhibitors might already have so improved ED that targeting XO to further improve ED could be futile. As an example of this possibility, the negative results of the PEACE (Prevention of Events with Angiotensin Converting Enzyme Inhibition) trial might have been because the ED of patients had been so improved already by statin therapy as to make ACE inhibitors ineffective. Therefore, a novel feature of our study was that we studied only optimally treated CAD patients to see whether XO inhibition can still improve ED and XO-induced OS in the presence of optimal CAD co-treatment. Only if allopurinol gives added value over contemporary treatment is it likely to be of practical therapeutic use.
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