Donald S.C. Ang

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.

Allopurinol Benefits Left Ventricular Mass and Endothelial Dysfunction in Chronic Kidney Disease

Allopurinol ameliorates endothelial dysfunction and arterial stiffness among patients without chronic kidney disease (CKD), but it is unknown if it has similar effects among patients with CKD. Furthermore, because arterial stiffness increases left ventricular afterload, any allopurinol-induced improvement in arterial compliance might also regress left ventricular hypertrophy (LVH). We conducted a randomized, double-blind, placebo-controlled, parallel-group study in patients with stage 3 CKD and LVH. We randomly assigned 67 subjects to allopurinol at 300 mg/d or placebo for 9 months; 53 patients completed the study. We measured left ventricular mass index (LVMI) with cardiac magnetic resonance imaging (MRI), assessed endothelial function by flow-mediated dilation (FMD) of the brachial artery, and evaluated central arterial stiffness by pulse-wave analysis. Allopurinol significantly reduced LVH (P=0.036), improved endothelial function (P=0.009), and improved the central augmentation index (P=0.015). This study demonstrates that allopurinol can regress left ventricular mass and improve endothelial function among patients with CKD. Because LVH and endothelial dysfunction associate with prognosis, these results call for further trials to examine whether allopurinol reduces cardiovascular events in patients with CKD and LVH.

Oxidative stress in renal dysfunction: mechanisms, clinical sequelae and therapeutic options

Oxidative stress has been increasingly linked to the high incidence of cardiovascular events in patients with chronic kidney disease (CKD), especially as traditional cardiovascular risk factors seem to not be able to account for the huge cardiovascular morbidity and mortality in this population group. Oxidative stress is increased in patients with renal impairment as a result of increased oxidant activity and reduced antioxidant capacity, and this is increased in a graded manner with increasing renal dysfunction. Inflammation, which is also present in CKD, further amplifies the oxidant generation process. The two clinical sequelae of oxidative stress are endothelial dysfunction and left ventricular hypertrophy, which have adverse cardiovascular consequences. With our new understanding of oxidative stress, it is now important to assess treatment options that reduce it in the hope that they reverse endothelial dysfunction and left ventricular hypertrophy and the clinical sequelae of these abnormalities.

A comparison between B-type natriuretic peptide, Global Registry of Acute Coronary Events (GRACE) score and their combination in ACS risk stratification

Background: In acute coronary syndrome (ACS), both the Global Registry of Acute Coronary Events (GRACE) score and B-type natriuretic peptide (BNP) predict cardiovascular events. However, it is unknown how BNP compares with GRACE and how their combination performs in ACS. Methods: The authors recruited 449 consecutive ACS patients and measured admission GRACE score and bedside BNP levels. The main outcome measure was all-cause mortality, readmission with ACS or congestive heart failure (defined as a cardiovascular event) at 10 months from presentation. Results: Of the 449 patients, 120 patients presented with ST-elevation myocardial infarction (MI) (27%). There were 90 cardiovascular events at 10 months. Both higher GRACE terciles and higher BNP terciles predicted cardiovascular events. There was a significant but only partial correlation between the GRACE score and log BNP (R = 0.552, p<0.001). On multivariate analyses, after adjusting for the GRACE score itself, increasing BNP terciles independently predicted cardiovascular events (second BNP tercile adjusted RR 2.28 (95% CI 1.15 to 4.51) and third BNP tercile adjusted RR 4.91 (95% CI 2.62 to 9.22)). Patients with high GRACE score-high BNP were more likely to experience cardiovascular events at 10 months (RR 6.00 (95% CI 2.40 to 14.83)) compared to those with high GRACE score-low BNP (RR 2.40 (95% CI 0.76 to 7.56)). Conclusion: In ACS, most but not all of our analyses suggest that BNP can predict cardiovascular events over and above the GRACE score. The combined use of both the GRACE score and BNP can identify a subset of ACS patients at particularly high risk. This implies that both the GRACE score and BNP reflect somewhat different risk attributes when predicting adverse prognosis in ACS and their synergistic use can enhance risk stratification in ACS to a small but potentially useful extent.

The effect of metformin on insulin resistance and exercise parameters in patients with heart failure

Chronic heart failure (CHF) is an insulin‐resistant state. The degree of insulin resistance (IR) correlates with disease severity and is associated with reduced exercise capacity. In this proof of concept study, we have examined the effect of metformin on IR and exercise capacity in non‐diabetic CHF patients identified to have IR.

Serial bedside B-type natriuretic peptide strongly predicts prognosis in acute coronary syndrome independent of echocardiographic abnormalities

BACKGROUND Elevated levels of B-type natriuretic peptide (BNP) are associated with adverse clinical outcomes in acute coronary syndrome (ACS), but several questions remain outstanding. Firstly, it has not yet been determined whether an additional BNP sample at 7 weeks post ACS would enhance risk prediction. Secondly, we assessed whether the prognostic potential of BNP in ACS could be explained by echocardiographic abnormalities such as left ventricular hypertrophy (LVH). METHODS We measured bedside BNP levels in 443 consecutive patients presenting with ACS and at 7 weeks outpatient follow-up. Main outcome measure was either all-cause mortality, readmission with ACS, or congestive heart failure) at 10 months from presentation. RESULTS Of the 443 patients, 120 patients presented with ST-elevation myocardial infarction (27%). There were 90 cardiovascular (CV) events at 10 months. Adjusting for age, sex, hypertension, diabetes mellitus, smoking status, renal dysfunction, left ventricular ejection fraction, and echocardiographic LVH elevated near patient BNP levels (>80 pg/mL) were still associated with subsequent CV events when measured on admission (adjusted relative risk [RR] 2.63 [95% CI 1.34-5.19)] and also at 7 weeks post ACS (adjusted RR 4.12 [95% CI 1.58-10.72]). Patients with persistent BNP elevation at 7 weeks were also at an increased risk of CV events compared to those with an initial high BNP which then fell (unadjusted RR 4.04 [95% CI 1.24-13.15]). CONCLUSION In ACS, bedside BNP levels predict CV events at 10 months, independent of many echocardiographic abnormalities including LVH. Furthermore, our study suggests that an additional 7 weeks post ACS BNP enhances risk stratification over and above a one-off high BNP at baseline.

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

BACKGROUND AND AIM Anaemia 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. DESIGN AND METHODS Haemoglobin 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). RESULTS The 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)]. CONCLUSION In 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.

The prognostic value of high sensitivity troponin T 7 weeks after an acute coronary syndrome

Objective The role of high sensitivity troponin T (hs-TnT) in the convalescence phase after an acute coronary syndrome (ACS) is unknown. The authors aim to assess the prognostic utility of a single hs-TnT level at 7-week post-ACS. Second, the authors evaluated whether any serial changes in hs-TnT between the index admission and 7 weeks post-ACS had any link with the prognosis. Third, the authors assessed whether the prognostic utility of hs-TnT is independent of various echocardiographic abnormalities. Methods The authors measured hs-TnT levels in 326 consecutive patients at 7 weeks after an ACS event. The composite end point of death from any cause or acute myocardial infarction was evaluated over a median duration of 30 months. Results A high 7-week hs-TnT (>14 ng/l) predicted adverse clinical outcomes independent of conventional risk factors, left ventricular dysfunction and left ventricular hypertrophy on echocardiography (adjusted RR: 2.69 (95% CI 1.45 to 5.00)). Patients with persistent hs-TnT elevation at 7 weeks were also at an increased risk of cardiovascular events compared with those with an initial high hs-TnT which then normalised (unadjusted RR 3.39 (95% CI 2.02 to 5.68)). Conclusion The authors have demonstrated the prognostic utility of a single 7-week hs-TnT measurement in routine ACS patients and that it could be used to assist medium term risk stratification in this patient cohort. In addition, the authors also showed that hs-TnT predicted long-term adverse prognosis independent of various echo parameters. Future studies should evaluate whether tailoring specific treatment interventions to higher risk individuals as identified by an elevated hs-TnT during the convalescence phase of ACS would improve clinical outcomes.

The prognostic value of a 7-week high sensitivity troponin T level after an acute coronary syndrome

Objective The role of high sensitivity troponin T (hs-TnT) in the convalescence phase after an acute coronary syndrome (ACS) is unknown. The authors aim to assess the prognostic utility of a single hs-TnT level at 7-week post-ACS. Second, the authors evaluated whether any serial changes in hs-TnT between the index admission and 7 weeks post-ACS had any link with the prognosis. Third, the authors assessed whether the prognostic utility of hs-TnT is independent of various echocardiographic abnormalities. Methods The authors measured hs-TnT levels in 326 consecutive patients at 7 weeks after an ACS event. The composite end point of death from any cause or acute myocardial infarction was evaluated over a median duration of 30 months. Results A high 7-week hs-TnT (>14 ng/l) predicted adverse clinical outcomes independent of conventional risk factors, left ventricular dysfunction and left ventricular hypertrophy on echocardiography (adjusted RR: 2.69 (95% CI 1.45 to 5.00)). Patients with persistent hs-TnT elevation at 7 weeks were also at an increased risk of cardiovascular events compared with those with an initial high hs-TnT which then normalised (unadjusted RR 3.39 (95% CI 2.02 to 5.68)). Conclusion The authors have demonstrated the prognostic utility of a single 7-week hs-TnT measurement in routine ACS patients and that it could be used to assist medium term risk stratification in this patient cohort. In addition, the authors also showed that hs-TnT predicted long-term adverse prognosis independent of various echo parameters. Future studies should evaluate whether tailoring specific treatment interventions to higher risk individuals as identified by an elevated hs-TnT during the convalescence phase of ACS would improve clinical outcomes.

Development and Validation of a Clinical Score to Identify Echocardiographic Left Ventricular Hypertrophy in Patients With Cardiovascular Disease

BACKGROUND Echocardiographic (echo) left ventricular hypertrophy (LVH) is an independent predictor of mortality. Despite this, screening for LVH in patients with overt cardiovascular diseases is not universally done. To help target echo screening for LVH in patient population, we developed and validated a simple clinical score to help identify those likely to have echo LVH. METHODS We performed two studies. The development cohort consisted of 267 patients with angina. The validation cohort consisted of 227 patients with peripheral arterial disease. RESULTS The prevalence of echo LVH in both patient cohorts was 50%. Six independent predictors of LVH were identified in the development cohort: age >65 years (1 point), body mass index >30 kg/m2 (1 point), history of hypertension (1 point), previous myocardial infarction (1 point), clinic blood pressure >130/80 mm Hg (1 point) and bundle branch block (BBB) on electrocardiogram (4 points). Our clinical score was strongly associated with the presence of LVH in the validation cohort. It also showed a significant continuous positive relationship (P trend <0.001 in males and P trend = 0.006 in females) with increasing quartiles of LV mass in both cohorts. In those without BBB, a modified clinical score performed equally well. CONCLUSION We have developed a simple clinical score which quantifies the chance that any patient with manifest cardiovascular disease has the added risk factor of LVH. This will help target precious echo resources toward individuals who are most likely to have this condition. This could potentially lead to better risk stratification in this patient population.