Downloaded from heart.bmj.com on August 21, 2014 - Published by group.bmj.com
Heart Online First, published on May 1, 2014 as 10.1136/heartjnl-2014-305683 Cardiac risk factors and prevention
ORIGINAL ARTICLE
Allopurinol reduces brachial and central blood pressure, and carotid intima-media thickness progression after ischaemic stroke and transient ischaemic attack: a randomised controlled trial P Higgins,1 M R Walters,1 H M Murray,2 K McArthur,1 A McConnachie,2 K R Lees,1 J Dawson1 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ heartjnl-2014-305683). 1
College of Medical, Veterinary and Life Sciences, Institute of Cardiovascular & Medical Sciences, University of Glasgow, Gardiner Institute, Western Infirmary, Glasgow, UK 2 College of Medical, Veterinary and Life Sciences, Institute of Health & Wellbeing, Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK Correspondence to Dr P Higgins, College of Medical, Veterinary and Life Sciences, Institute of Cardiovascular & Medical Sciences, University of Glasgow, Gardiner Institute, Western Infirmary, Glasgow G11 6NT, UK; [email protected] PH and MRW are co-first authors. Received 19 February 2014 Revised 18 March 2014 Accepted 29 March 2014
To cite: Higgins P, Walters MR, Murray HM, et al. Heart Published Online First: [ please include Day Month Year] doi:10.1136/ heartjnl-2014-305683
ABSTRACT Objective Central blood pressure (CBP) and carotid intima-media thickness (CIMT) are surrogate measures of cardiovascular risk. Allopurinol reduces serum uric acid and oxidative stress and improves endothelial function and may therefore reduce CBP and CIMT progression. This study sought to ascertain whether allopurinol reduces CBP, arterial stiffness and CIMT progression in patients with ischaemic stroke or transient ischaemic attack (TIA). Methods We performed a randomised, double-blind, placebo-controlled study, examining the effect of 1-year treatment with allopurinol (300 mg daily), on change in CBP, arterial stiffness and CIMT progression at 1 year and change in endothelial function and circulating inflammatory markers at 6 months. Patients aged over 18 years with recent ischaemic stroke or TIA were eligible. Results Eighty participants were recruited, mean age 67.8 years (SD 9.4). Systolic CBP [−6.6 mm Hg (95% CI −13.0 to −0.3), p=0.042] and augmentation index [−4.4% (95% CI −7.9 to −1.0), p=0.013] were each lower following allopurinol treatment compared with placebo at 12 months. Progression in mean common CIMT at 1 year was less in allopurinol-treated patients compared with placebo [between-group difference [−0.097 mm (95% CI −0.175 to −0.019), p=0.015]. No difference was observed for measures of endothelial function. Conclusions Allopurinol lowered CBP and reduced CIMT progression at 1 year compared with placebo in patients with recent ischaemic stroke and TIA. This extends the evidence of sustained beneficial effects of allopurinol to these prognostically significant outcomes and to the stroke population, highlighting the potential for reduction in cardiovascular events with this treatment strategy. Trial registration number ISRCTN11970568.
Elevated serum uric acid (UA) is associated with increased risk of cardiovascular disease3 and adverse outcomes following ischaemic stroke.4 Allopurinol reduces serum UA through inhibition of the xanthine oxidoreductase (XO) enzymatic system, which is responsible for the final steps in purine metabolism. Further, XO inhibition reduces the reactive oxygen species formed through action of the enzyme and may thus reduce vascular oxidative stress, which is implicated in atherogenesis.5 Allopurinol may therefore provide benefits in addition to or independent of its effects on UA.6 Systematic review and meta-analysis of studies examining XO inhibition has demonstrated beneficial effects on endothelial function and other surrogate measures of cardiovascular function.7 Further, following stroke, allopurinol has been reported to reduce both arterial stiffness8 and markers of inflammation9 and also increases nitric oxide bioavailability in patients with type 2 diabetes.10 More recently, treatment with high-dose allopurinol was found to induce regression in left ventricular hypertrophy (LVH)11 and improve exercise capacity in patients with coronary artery disease.12 However, studies examining XO inhibition have typically been of limited duration and there are no prolonged studies in the stroke patient population, or on measures of atherosclerosis. We sought to address this evidence gap by performing a randomised, double-blind, placebocontrolled study with a 1-year treatment duration, which examined the effect of allopurinol 300 mg daily on change in central blood pressure (BP), arterial stiffness, endothelial function and circulating markers of low-grade inflammation and also provided pilot data concerning the effect of allopurinol on carotid intima-media thickness (CIMT) progression.
BACKGROUND
METHODS Study design
Despite secondary preventative measures, recurrent stroke events remain common; approximately 13% of participants suffered recurrent stroke in recent secondary preventative trials,1 and 40% of those with transient ischaemic attack (TIA) experienced recurrent cardiovascular events during long-term follow-up.2 Novel strategies are needed to reduce this burden.
We performed a randomised, double-blind, placebo-controlled trial, comparing allopurinol 300 mg once daily with matched placebo in an adult population with recent ischaemic stroke or TIA. Patients were followed up for 12 months and underwent repeated measurement of CIMT, arterial haemodynamics and endothelial function.
Higgins P, et Article al. Heart 2014;0:1–8. doi:10.1136/heartjnl-2014-305683 1 Copyright author (or their employer) 2014. Produced by BMJ Publishing Group Ltd (& BCS) under licence.
Downloaded from heart.bmj.com on August 21, 2014 - Published by group.bmj.com
Cardiac risk factors and prevention Study population Patients aged over 18 years with ischaemic stroke or TIA, within the past year, were eligible for inclusion. Principal exclusion criteria were >70% extra-cranial internal carotid artery stenosis, significant comorbidity likely to cause death within 12 months and either indication for, or contraindication to (including estimated glomerular filtration rate
Heart Online First, published on May 1, 2014 as 10.1136/heartjnl-2014-305683 Cardiac risk factors and prevention
ORIGINAL ARTICLE
Allopurinol reduces brachial and central blood pressure, and carotid intima-media thickness progression after ischaemic stroke and transient ischaemic attack: a randomised controlled trial P Higgins,1 M R Walters,1 H M Murray,2 K McArthur,1 A McConnachie,2 K R Lees,1 J Dawson1 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ heartjnl-2014-305683). 1
College of Medical, Veterinary and Life Sciences, Institute of Cardiovascular & Medical Sciences, University of Glasgow, Gardiner Institute, Western Infirmary, Glasgow, UK 2 College of Medical, Veterinary and Life Sciences, Institute of Health & Wellbeing, Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK Correspondence to Dr P Higgins, College of Medical, Veterinary and Life Sciences, Institute of Cardiovascular & Medical Sciences, University of Glasgow, Gardiner Institute, Western Infirmary, Glasgow G11 6NT, UK; [email protected] PH and MRW are co-first authors. Received 19 February 2014 Revised 18 March 2014 Accepted 29 March 2014
To cite: Higgins P, Walters MR, Murray HM, et al. Heart Published Online First: [ please include Day Month Year] doi:10.1136/ heartjnl-2014-305683
ABSTRACT Objective Central blood pressure (CBP) and carotid intima-media thickness (CIMT) are surrogate measures of cardiovascular risk. Allopurinol reduces serum uric acid and oxidative stress and improves endothelial function and may therefore reduce CBP and CIMT progression. This study sought to ascertain whether allopurinol reduces CBP, arterial stiffness and CIMT progression in patients with ischaemic stroke or transient ischaemic attack (TIA). Methods We performed a randomised, double-blind, placebo-controlled study, examining the effect of 1-year treatment with allopurinol (300 mg daily), on change in CBP, arterial stiffness and CIMT progression at 1 year and change in endothelial function and circulating inflammatory markers at 6 months. Patients aged over 18 years with recent ischaemic stroke or TIA were eligible. Results Eighty participants were recruited, mean age 67.8 years (SD 9.4). Systolic CBP [−6.6 mm Hg (95% CI −13.0 to −0.3), p=0.042] and augmentation index [−4.4% (95% CI −7.9 to −1.0), p=0.013] were each lower following allopurinol treatment compared with placebo at 12 months. Progression in mean common CIMT at 1 year was less in allopurinol-treated patients compared with placebo [between-group difference [−0.097 mm (95% CI −0.175 to −0.019), p=0.015]. No difference was observed for measures of endothelial function. Conclusions Allopurinol lowered CBP and reduced CIMT progression at 1 year compared with placebo in patients with recent ischaemic stroke and TIA. This extends the evidence of sustained beneficial effects of allopurinol to these prognostically significant outcomes and to the stroke population, highlighting the potential for reduction in cardiovascular events with this treatment strategy. Trial registration number ISRCTN11970568.
Elevated serum uric acid (UA) is associated with increased risk of cardiovascular disease3 and adverse outcomes following ischaemic stroke.4 Allopurinol reduces serum UA through inhibition of the xanthine oxidoreductase (XO) enzymatic system, which is responsible for the final steps in purine metabolism. Further, XO inhibition reduces the reactive oxygen species formed through action of the enzyme and may thus reduce vascular oxidative stress, which is implicated in atherogenesis.5 Allopurinol may therefore provide benefits in addition to or independent of its effects on UA.6 Systematic review and meta-analysis of studies examining XO inhibition has demonstrated beneficial effects on endothelial function and other surrogate measures of cardiovascular function.7 Further, following stroke, allopurinol has been reported to reduce both arterial stiffness8 and markers of inflammation9 and also increases nitric oxide bioavailability in patients with type 2 diabetes.10 More recently, treatment with high-dose allopurinol was found to induce regression in left ventricular hypertrophy (LVH)11 and improve exercise capacity in patients with coronary artery disease.12 However, studies examining XO inhibition have typically been of limited duration and there are no prolonged studies in the stroke patient population, or on measures of atherosclerosis. We sought to address this evidence gap by performing a randomised, double-blind, placebocontrolled study with a 1-year treatment duration, which examined the effect of allopurinol 300 mg daily on change in central blood pressure (BP), arterial stiffness, endothelial function and circulating markers of low-grade inflammation and also provided pilot data concerning the effect of allopurinol on carotid intima-media thickness (CIMT) progression.
BACKGROUND
METHODS Study design
Despite secondary preventative measures, recurrent stroke events remain common; approximately 13% of participants suffered recurrent stroke in recent secondary preventative trials,1 and 40% of those with transient ischaemic attack (TIA) experienced recurrent cardiovascular events during long-term follow-up.2 Novel strategies are needed to reduce this burden.
We performed a randomised, double-blind, placebo-controlled trial, comparing allopurinol 300 mg once daily with matched placebo in an adult population with recent ischaemic stroke or TIA. Patients were followed up for 12 months and underwent repeated measurement of CIMT, arterial haemodynamics and endothelial function.
Higgins P, et Article al. Heart 2014;0:1–8. doi:10.1136/heartjnl-2014-305683 1 Copyright author (or their employer) 2014. Produced by BMJ Publishing Group Ltd (& BCS) under licence.
Downloaded from heart.bmj.com on August 21, 2014 - Published by group.bmj.com
Cardiac risk factors and prevention Study population Patients aged over 18 years with ischaemic stroke or TIA, within the past year, were eligible for inclusion. Principal exclusion criteria were >70% extra-cranial internal carotid artery stenosis, significant comorbidity likely to cause death within 12 months and either indication for, or contraindication to (including estimated glomerular filtration rate
