Awsan Noman

Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial

Summary Background Experimental evidence suggests that xanthine oxidase inhibitors can reduce myocardial oxygen consumption for a particular stroke volume. If such an effect also occurs in man, this class of inhibitors could become a new treatment for ischaemia in patients with angina pectoris. We ascertained whether high-dose allopurinol prolongs exercise capability in patients with chronic stable angina. Methods 65 patients (aged 18–85 years) with angiographically documented coronary artery disease, a positive exercise tolerance test, and stable chronic angina pectoris (for at least 2 months) were recruited into a double-blind, randomised, placebo-controlled, crossover study in a hospital and two infirmaries in the UK. We used computer-generated randomisation to assign patients to allopurinol (600 mg per day) or placebo for 6 weeks before crossover. Our primary endpoint was the time to ST depression, and the secondary endpoints were total exercise time and time to chest pain. We did a completed case analysis. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 82040078. Findings In the first treatment period, 31 patients were allocated to allopurinol and 28 were analysed, and 34 were allocated to placebo and 32 were analysed. In the second period, all 60 patients were analysed. Allopurinol increased the median time to ST depression to 298 s (IQR 211–408) from a baseline of 232 s (182–380), and placebo increased it to 249 s (200–375; p=0·0002). The point estimate (absolute difference between allopurinol and placebo) was 43 s (95% CI 31–58). Allopurinol increased median total exercise time to 393 s (IQR 280–519) from a baseline of 301 s (251–447), and placebo increased it to 307 s (232–430; p=0·0003); the point estimate was 58 s (95% CI 45–77). Allopurinol increased the time to chest pain from a baseline of 234 s (IQR 189–382) to 304 s (222–421), and placebo increased it to 272 s (200–380; p=0·001); the point estimate was 38 s (95% CI 17–55). No adverse effects of treatment were reported. Interpretation Allopurinol seems to be a useful, inexpensive, well tolerated, and safe anti-ischaemic drug for patients with angina. Funding British Heart Foundation.

High-Dose Allopurinol Reduces Left Ventricular Mass in Patients With Ischemic Heart Disease

OBJECTIVESnThis study sought to ascertain if high-dose allopurinol regresses left ventricular mass (LVM) in patients with ischemic heart disease (IHD).nnnBACKGROUNDnLV hypertrophy (LVH) is common in patients with IHD including normotensive patients. Allopurinol, a xanthine oxidase inhibitor, has been shown to reduce LV afterload in IHD and may therefore also regress LVH.nnnMETHODSnA randomized, double-blind, placebo-controlled, parallel group study was conducted in 66 patients with IHD and LVH, comparing 600 mg/day allopurinol versus placebo therapy for 9 months. The primary outcome measure was change in LVM, assessed by cardiac magnetic resonance imaging (CMR). Secondary outcome measures were changes in LV volumes by CMR, changes in endothelial function by flow-mediated dilation (FMD), and arterial stiffness by applanation tonometry.nnnRESULTSnCompared to placebo, allopurinol significantly reduced LVM (allopurinol -5.2 ± 5.8 g vs. placebo -1.3 ± 4.48 g; p = 0.007) and LVM index (LVMI) (allopurinol -2.2 ± 2.78 g/m(2) vs. placebo -0.53 ± 2.5 g/m(2); p = 0.023). The absolute mean difference between groups for change in LVM and LVMI was -3.89 g (95% confidence interval: -1.1 to -6.7) and -1.67 g/m(2) (95% confidence interval: -0.23 to -3.1), respectively. Allopurinol also reduced LV end-systolic volume (allopurinol -2.81 ± 7.8 mls vs. placebo +1.3 ± 7.22 mls; p = 0.047), improved FMD (allopurinol +0.82 ± 1.8% vs. placebo -0.69 ± 2.8%; p = 0.017) and augmentation index (allopurinol -2.8 ± 5.1% vs. placebo +0.9 ± 7%; p = 0.02).nnnCONCLUSIONSnHigh-dose allopurinol regresses LVH, reduces LV end-systolic volume, and improves endothelial function in patients with IHD and LVH. This raises the possibility that allopurinol might reduce future cardiovascular events and mortality in these patients. (Does a Drug Allopurinol Reduce Heart Muscle Mass and Improve Blood Vessel Function in Patients With Normal Blood Pressure and Stable Angina?; ISRCTN73579730).

High-potency statin and ezetimibe use and mortality in survivors of an acute myocardial infarction: a population-based study

Objective To determine all-cause mortality in patients with a first myocardial infarct who were treated with simvastatin compared with high-potency statin and simvastatin/ezetimibe combination. Background Despite statin use, residual cardiovascular risk remains. Therapeutic options include more potent statins or addition of ezetimibe. There is no clinical outcome data on the use of ezetimibe in such patients. Methods Retrospective longitudinal study using the United Kingdom General Practice Research Database. Patients who had survived 30u2005days after their first acute myocardial infarct (AMI), had not received prior statin or ezetimibe therapy and were started on a statin within 30u2005days of AMI were included. Three groups were identified according to their follow-up: (i) simvastatin monotherapy; (ii) high-potency statin group (patients who started on simvastatin and switched to atorvastatin or rosuvastatin); and (iii) ezetimibe/statin combination group (patients who received ezetimibe in addition to statin). Results 9597 patients (57% male, mean age of 65±13u2005years) matched study criteria: simvastatin (n=6990 (72.8%)); high-potency statin (n=1883, (19.6%)); and ezetimibe/statin combination (n=724 (7.5%)). During a mean follow-up of 3.2u2005years, there were 1134 (12%) deaths. In the multivariate proportional hazards model, the adjusted HR for high-potency statin and ezetimibe group were 0.72 (95% CI 0.59 to 0.88, p<0.001) and 0.96 (95% CI 0.64 to 1.43, p=0.85), respectively. A similar result was also obtained in the propensity score analysis that took into account covariates that predicted drug treatment groups. Conclusions Patients switched to a high-potency statin had a significantly reduced mortality compared with simvastatin monotherapy. There was no observed mortality benefit in the ezetimibe group.

The prognostic significance of early and late anaemia in acute coronary syndrome

BACKGROUND AND AIMnAnaemia in acute coronary syndrome (ACS) is a common and strong independent risk factor but it is unknown whether early anaemia is transient or whether it persists over the subsequent weeks. We also sought to evaluate whether late anaemia carries the similar prognostic significance as baseline anaemia. Another unknown is whether haemoglobin improves risk stratification over and above the GRACE score.nnnDESIGN AND METHODSnHaemoglobin levels were prospectively measured in 448 consecutive patients presenting with ACS and at 7-weeks follow-up. Cardiovascular endpoints were defined as death or acute myocardial infarction (AMI) over a median duration of 30 months (range 1-50).nnnRESULTSnThe prevalence of anaemia on admission was 20% and this increased to 40% at 7-weeks follow-up. New anaemia occurred in 31% of patients. Baseline anaemia predicted CV endpoints independent of the admission GRACE (Global Registry of Acute Coronary Events) score [adjusted RR 2.54 (95% CI 1.73-3.71)]. Anaemia at 7-weeks follow-up was also a strong predictor of adverse outcomes [adjusted RR 1.67 (95% CI 1.04-2.69)]. Patients with persistent anaemia at 7 weeks were at an increased risk of death or AMI compared to those with persistently normal haemoglobin [unadjusted RR 3.58 (95% CI 2.04-6.29)].nnnCONCLUSIONnIn ACS, the prevalence of anaemia doubles from admission to 7-weeks follow-up (40%). Not only did baseline anaemia predict long-term prognosis independent of the admission GRACE score, but haemoglobin at 7-weeks post-ACS was also a simple independent predictor of adverse prognosis.

Right ventricular pacing impairs endothelial function in man

AIMSnClinical trial data show that right ventricular pacing worsens cardiovascular outcomes. The underlying pathophysiology of this is undetermined. We studied the effects of right ventricular pacing on cardiac measures of vascular health (endothelial function), ventricular wall stress (B-type natriuretic peptide), and cardiac reserve (cardiac output response to exercise) in subjects with pacemakers.nnnMETHODS AND RESULTSnTwenty-two subjects [mean age 68.4 ± 8.8 (SD) years] with dual-chamber pacemakers implanted for sino-atrial disease were studied in a randomized crossover study comparing minimal right ventricular pacing [RVP-min; pacing with long atrioventricular delay (AVD)] to maximal right ventricular pacing (RVP-max; pacing with short AVD). Endothelial function was measured with reactive hyperaemia peripheral arterial tonometry. Cardiac output at rest and during exercise was determined using an inert gas rebreathing method. Right ventricular pacing was significantly higher in RVP-max when compared with RVP-min (90 ± 16 vs. 15 ± 20%, P < 0.001). Reactive hyperaemia peripheral arterial tonometry index was significantly lower after RVP-max vs. RVP-min (1.73 ± 0.33 vs. 1.96 ± 0.37, P < 0.05). B-type natriuretic peptide was not significantly different between pacing modes (113 ± 80 vs. 104 ± 108 pg/mL, P = NS). Cardiac output at peak exercise was significantly lower during RVP-max (7.65 ± 3.15 vs. 7.05 ± 2.61 L/min, P < 0.05).nnnCONCLUSIONnRight ventricular pacing is associated with worsened endothelial function and cardiac reserve.

A new use for B-type natriuretic peptide: to detect myocardial ischaemia in non-heart failure patients

B-type natriuretic peptide (BNP) is a natriuretic pep tide released primarily by ventricular myocytes in response to various physiological and pathological stimuli. In addition to its established diagnostic role in patients with heart failure, a growing body of evidence suggests that raised levels of BNP in the absence of heart failure can indicate myocardial ischaemia. This appears to be the case in patients with symptomatic, and even asymptomatic coronary artery disease (CAD). In this review, we discuss the current evidence supporting the role of BNP as a simple marker of cardiac ischaemia and CAD. We also propose some therapeutic interventions that may be use ful when BNP detects silent myocardial ischaemia. Br J Diabetes Vasc Dis 2010;10:78-82

115 The Impact of Smoking on Mortality Following Percutaneous Coronary Intervention-an Observational Study

Aim To assess the impact of smoking on mortality following percutaneous coronary intervention (PCI). Methods A total of 13041 patients underwent PCI between 2008 and 2011 at two large tertiary centres. Data on smoking status were missing in 385 patients. The remaining 12656 patients were included in this analysis. Patients were divided into three groups according to their smoking status at the time of index PCI procedure: non- smokers (n = 4288, 33.9%), ex-smokers (n = 4806, 38.0%) and current smokers (n = 3562, 28.1%). Results Current smokers underwent PCI at a younger age (mean ± SD) and more frequently for acute coronary syndrome (ACS) (57 ± 11 years, 84.1% for ACS) compared to non-smokers (67 ± 12 years, 62.9%) and ex-smokers (67 ± 11 years, 57.0%), p < 0.0001 for both. Overall 30-day mortality rate was (1.8%). In a logistic regression model adjusted for several confounders, the adjusted odds ratios (95% confidence intervals [CI]) for 30-day mortality were 0.98 (0.70–1.38) in ex-smokers and 1.60 (1.10–2.32) in current smokers compared to non-smokers. Overall mortality rate between 30 days and 6 months post PCI was 1.5%. In the multiple Cox proportional hazards model, the adjusted hazard ratios (95% CI) for mortality between 30 days and 6 months were 1.19 (0.84–1.67) in ex-smokers and 1.03 (0.65–1.65) in current smokers compared to non-smokers. Conclusions This large observational study of unselected, real-world patients demonstrates a younger age at presentation for PCI and increased 30-day post-PCI mortality in current smokers compared to ex-smokers and non-smokers. Ex-smokers have a similar age at presentation and post PCI mortality outcome as non-smokers. These findings further re-enforce the public health message regarding the harmful effect of smoking and the benefits of smoking cessation in patients undergoing PCI.

Pneumonitis and pulmonary haemorrhage after acute myocardial infarction

A 55-year-old man presented with acute ST-elevation myocardial infarction. He received rescue angioplasty with one drug eluting stent. He developed marked breathlessness and haemoptysis two days later. Investigations led to the diagnosis of pulmonary haemorrhage, possibly from pneumonitis caused by ticagrelor. He was successfully managed with high-dose steroids and ticagrelor was replaced with clopidogrel. On stopping the steroids a month later, mild haemoptysis recurred and this was managed conservatively. Pneumonitis and pulmonary haemorrhage is rarely reported with acute myocardial infarction, but poses serious challenge to the patient and the clinician. Diagnosis may be delayed as breathlessness can occur due to myriad causes after myocardial infarction. Interrupting dual anti-platelet therapy after angioplasty could lead to devastating stent thrombosis.

136 HIGH DOSE ALLOPURINOL IMPROVES ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH ISCHAEMIC HEART DISEASE AND LEFT VENTRICULAR HYPERTROPHY BUT DOES NOT MATCH AGE AND GENDER MATCHED CONTROLS

Background Endothelial dysfunction is a poor prognostic marker in patients with ischaemic heart disease (IHD). Superoxide free radicals, which are generated by xanthine oxidase, contribute to oxidative stress and leads to the development of endothelial dysfunction. Aim of this sub-study was to investigate if high dose allopurinol, a xanthine oxidase inhibitor, could improve endothelial function in patients with IHD and left ventricular hypertrophy (LVH) to the same level of age and gender matched healthy volunteers. Methods 66 patients with IHD and LVH were recruited into a randomised, double blind, placebo controlled parallel study. They received 600u2005mg/day allopurinol or placebo therapy over a 9u2005month follow up period. Endothelial function tests were performed at baseline, 6u2005months and 9u2005months visit. In addition, thirty age and gender matched healthy volunteers (HV) attended a single study visit for endothelial function tests. Endothelial function was assessed using flow-mediated dilatation (FMD) of the brachial artery and arterial stiffness measured using pulse wave analysis. Results 60 patients completed the main study (31 active, 29 placebo). At baseline, the HV had a significantly greater FMD and lower AIx compared to the allopurinol group. Allopurinol significantly improved brachial artery FMD (ΔFMD: +0.82%±1.8% allopurinol vs—0.69%±2.8% placebo; p=0.017) and central augmentation index (Δ AIx: −2.8%±5.1% allopurinol vs +0.9%±7% placebo; p=0.02). However, after 9u2005months of allopurinol therapy, their absolute endothelial function did not match that of age and gender matched healthy volunteers (FMD: 4.94±2.2% allopurinol vs 6.3±3.74% HV, p=0.092; AIx: 17.4±8.6% vs 12.8±11% HV, p=0.071). Conclusions In conclusion, high dose allopurinol improves endothelial dysfunction in patients with ischaemic heart disease and left ventricular hypertrophy but their absolute endothelial function does not match age and gender matched healthy volunteers.

High-dose allopurinol in patients with stable angina pectoris. Authors' reply

1298 www.thelancet.com Vol 376 October 16, 2010 I found your Editorial on home births disconcerting: “Women have the right to choose when and where to give birth, but do not have the right to put their baby at risk. There are competing interests that need to be weighed.” This statement overlooks a crucial distinction between rights and interests. All human beings have an interest in, not a right to, the best possible treatment—whether from the state, the health-care system, or their parents. Thus, babies have an interest in, not a right to, the safest possible birth. By contrast, all human beings— pregnant ones included—have a right to, rather than an interest in, freedom and self-determination. The scope of this right is fuzzy, limited by the rights of others, and certainly not all-encompassing. But it must and is widely recognised to include the right to capably refuse interference with one’s body—with or without a blossoming human being inside. Rights and interests should not be confl ated. And where they are in confl ict, rights generally hold trump. Why, though, is your Editorial disconcerting, rather than merely erroneous? The reason consists of the practical and detrimental consequences of adopting this stance. Reducing rights to mere interests that can be weighed changes the mother from the owner of to a mere factor in the perinatal decision process. This is directly deleterious to her right to self-determination. The weighing of interests, risks, and outcomes is part of a capable exercise of human autonomy, not the other way around.