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1. Iqbal Malik, Editor

## ISCHAEMIC HEART DISEASE

Direct stent or plain old balloon for primary angioplasty? ▸ Two independent reviewers selected and extracted data from identified randomised trials of direct stenting or balloon angioplasty for acute myocardial infarction (MI). The outcomes were mortality at 30 days, 6 months, and 12 months; recurrent events; and bleeding. Nine trials with a total of 4433 patients fulfilled the inclusion criteria. The odds ratios for mortality after stenting as compared with balloon angioplasty were 1.17 (95% confidence interval (CI) 0.78 to 1.74) at 30 days and 1.09 (95% CI 0.80 to 1.50) at 12 months (p value for heterogeneity > 0.1 for each comparison). The odds ratios for reinfarction after stenting as compared with balloon angioplasty were 0.52 (95% CI 0.31 to 0.87) at 30 days and 0.67 (95% CI 0.45 to 0.99) at 12 months; for target vessel revascularisation, they were 0.46 (95% CI 0.34 to 0.61) at 30 days, and 0.48 (95% CI 0.39 to 0.59) at 12 months (p value for heterogeneity > 0.1 for all estimates with the exception of reinfarction at 12 months where p  =  0.08). The odds ratio for postinterventional bleeding complications after stenting as compared with balloon angioplasty was 1.34 (95% CI 0.95 to 1.88; p value for heterogeneity > 0.1). Compared with balloon angioplasty, primary stenting is not associated with lower mortality, but is associated with a lower risk of reinfarction and target vessel revascularisation. Part of the effect may have been due to the use of ticlopidine and clopidogrel in the stent arm, but this is not proven.

Folic acid fortification: does it reduce mortality? ▸ In 1998, the US Food and Drug Administration mandated the fortification of food products with folic acid. The effect of this rule on mortality associated with homocysteine concentrations in patients with coronary artery disease is unknown. A total of 2481 patients were divided into prefortification (1994 to 1997, n  =  1595) and postfortification (1998 to 1999, n  =  886) groups, and were also classified according to baseline homocysteine values (normal to low, intermediate, and high). After implementation of the fortification rule, median homocysteine concentrations declined from 13.8 to 12.3 μmol/l (p < 0.001), and the proportion of patients with high homocysteine concentrations (> 15 μmol/l) decreased from 41% (n  =  650) to 28% (n  =  249) (p < 0.001). Overall, homocysteine was a modest risk factor for mortality (adjusted relative risk (RR) 1.03 per μmol/l, 95% CI 1.01 to 1.05, p  =  0.006). There was no significant interaction between fortification status and homocysteine category with mortality (p value for interaction  =  0.85). Two year mortality was reduced minimally (and not significantly) (7.8% to 7.2%; RR 0.93, 95% CI 0.68 to 1.27, p  =  0.63; adjusted RR 0.97, 95% CI 0.68 to 1.40), but was consistent with the expectation of a modest reduction in homocysteine concentrations. Other treatments would be likely to have much greater benefit than folic acid.

Reducing homocysteine produces no dramatic reduction in stroke or MI ▸ Six hundred and eighty adults with non-disabling cerebral infarction received best medical and surgical care plus a daily multivitamin. Patients were randomly assigned to receive once daily doses of the high dose formulation (n  =  1827), containing 25 mg of pyridoxine, 0.4 mg of cobalamin, and 2.5 mg of folic acid; or the low dose formulation (n  =  1853). Mean reduction of total homocysteine was 2 μmol/l greater in the high dose group than in the low dose group, but there was no treatment effect on any end point. The unadjusted risk ratio for any stroke, coronary heart disease (CHD) event, or death was 1.0 (95% CI 0.8 to 1.1), with chances of an event within two years of 18.0% in the high dose group and 18.6% in the low dose group. The risk of ischaemic stroke within two years was 9.2% for the high dose and 8.8% for the low dose groups (risk ratio 1.0, 95% CI 0.8 to 1.3) (p  =  0.80 by log rank test of the primary hypothesis of difference in ischaemic stroke between treatment groups). So, moderate reduction of total homocysteine after non-disabling cerebral infarction had no effect on vascular outcomes during the two years of follow up.

Discharge four days post-MI is possible, but is not happening ▸ The definition of “early” discharge post-MI has evolved over the years: from 15 days in the 1970s to the current American College of Cardiology (ACC)/American Heart Association (AHA), and European Society of Cardiology (ESC) guidelines recommendation that patients with uncomplicated acute MI be considered for discharge within four days of admission. The study population consisted of 54 174 patients enrolled in GUSTO-I, GUSTO-III, and ASSENT-2 studies (enrolment period 1990–98) in the USA, Canada, Australia, New Zealand, Belgium, France, Germany, Spain, and Poland. Patients with uncomplicated acute MI who were eligible for early discharge on the basis of previously established criteria were defined, and the extent to which these patients were discharged early (day 4) assessed. Patients in all European countries had significantly longer stays than did those from non-European countries. Over the study period, the number of eligible patients discharged on or before day 4 increased in the USA, Canada, Australia, and New Zealand. Despite this increase, no more than 40% of patients who were eligible for early discharge were actually discharged early. The rate of early discharge of eligible patients was consistently low (< 2%) in Belgium, France, Germany, Spain, and Poland. In ASSENT-2, which is the most recent trial in this study, the number of potentially unnecessary hospital days (per 100 patients enrolled) ranged from 65 in New Zealand to 839 in Germany.

What is the best way to “facilitate” primary angioplasty? ▸ A regimen consisting of the combination of half dose reteplase plus abciximab has been shown to restore brisk blood flow better in the infarct related artery compared with treatment with full dose reteplase. In a randomised trial, patients of both treatment groups received intravenous abciximab administered as a bolus of 0.25 mg/kg of body weight followed with a continuous infusion of 0.125 μg/kg per minute (maximum dose 10 μg/min) for 12 hours. Patients assigned to combination therapy, reteplase plus abciximab, received reteplase administered in two intravenous bolus doses of 5 U (30 minutes apart). The first bolus of reteplase was administered immediately after the bolus of abciximab. All patients also received intravenous 500 mg aspirin and 60 U/kg body weight heparin (maximum dose 5000 U). There was no difference in outcomes with the two regimens in terms of infarct size or prognosis despite better TIMI 3 flow rates in the combined treatment group. The results of FINESSE and ASSENT-4 trials will add to the debate further.

## HEART FAILURE

Predicting mortality in heart failure ▸ Neurohormonal values are the best predictors of heart failure outcome but are not measured in most patients. A multivariate statistical model to predict mortality using clinical variables was developed in a random sample (n  =  4277 patients) of the 6422 patients enrolled in the digitalis investigation group trial who had a depressed ejection fraction (⩽45%), were in sinus rhythm, and were taking angiotensin converting enzyme (ACE) inhibitors. The model was then validated in the remaining 2145 patients. Total mortality in the derivation sample was 11.2% (n  =  480) at 12 months and 29.9% (n  =  1277) at 36 months. Lower ejection fraction, worse renal function, cardiomegaly (CT ratio > 50%), worse functional class, signs or symptoms of heart failure, lower blood pressure, and lower body mass index were associated with reduced 12 month survival. This model provided good predictions of mortality in the verification sample. The same variables, along with age and the baseline use of nitrates, were also predictive of 36 month mortality. The appendix to the paper gives details of how to calculate three year mortality.

## GENERAL CARDIOLOGY

Diagnostic pathway for pulmonary embolism ▸ This study of 956 patients showed that a diagnostic strategy combining clinical probability, D-dimer measurement, venous ultrasonography, and helical computed tomography (CT) in a stepwise fashion was safe and effective in outpatients suspected of pulmonary embolism. However, this series was not designed to test the hypothesis that single slice helical CT alone is safe for ruling out pulmonary embolism, and venous ultrasonography should be combined with CT to compensate for its limited sensitivity pending the results of ongoing studies of multidetector technology. Only 1% of patients not anticoagulated because of “exclusion” of pulmonary embolism developed thromboembolism during three months of follow up. No patients with negative D-dimer test (value < 500 μg/l) developed thromboembolism.

BNP reduces costs of assessment and duration of stay in patients with dyspnoea in A&E ▸ In a randomised controlled trial, 225 patients were assigned to a diagnostic strategy involving the measurement of B type natriuretic peptide (BNP) concentrations with the use of a rapid bedside assay, and 227 were assessed in a standard manner. Baseline demographic and clinical characteristics were well matched between the two groups. The use of BNP values reduced the need for hospitalisation (75% of BNP group v 85% of control group, p  =  0.008) and intensive care (15% in BNP group v 24%, p  =  0.01). The median time to discharge was 8.0 days in the BNP group and 11.0 days in the control group (p  =  0.001). The mean total cost of treatment was $5410 (95% CI$4516 to $6304) in the BNP group, compared with$7264 (95% CI $6301 to$8227) in the control group (p  =  0.006). The respective 30 day mortality rates were 10% and 12% (p  =  0.45).

Constriction occurs in over 5% of cases of tamponade ▸ A total of 1184 patients with pericarditis were evaluated, 218 of whom had tamponade. Of these 218, 190 underwent combined pericardiocentesis and catheterisation. Fifteen of these patients (6.7% of all cases of tamponade) had effusive–constrictive pericarditis and were included in the study. All patients presented with clinical tamponade; however, concomitant constriction was recognised in only seven patients. At catheterisation, all patients had raised intrapericardial pressure (median 12 mm Hg; interquartile range 7 to 18 mm Hg) and raised right atrial and end diastolic right and left ventricular pressures. After pericardiocentesis, the intrapericardial pressure decreased (median value −5 mm Hg; interquartile range −5 to 0 mm Hg), whereas right atrial and end diastolic right and left ventricular pressures, although slightly reduced, remained raised, with a dip–plateau morphology. The causes were diverse, and death was mainly related to the underlying disease. Pericardiectomy was required in seven patients, all of whom had involvement of the visceral pericardium, requiring careful stripping. Three patients had spontaneous resolution.

Distal protection devices used in carotid stenting ▸ Distal protection devices are increasingly used in coronary intervention. Whereas a small troponin rise can be swept under the carpet, an embolism to the brain cannot be ignored, explaining the increasing use of distal protection during carotid stenting. This study presents data from a multinational registry. The protection device was positioned successfully in 793 (98.2%) of the 808 attempted carotid vessels. Neurologic complications occurred within 30 days after 46 procedures (5.6%), including seven major strokes, 17 minor strokes, and 22 transient ischaemic attacks. There were four deaths (one following a major stroke). The 30 day incidence of stroke and death was 3.3% (27/815). The rate of stroke or death was 3.8% (8/213) for symptomatic lesions and 3.2% (19/602) for asymptomatic lesions (p  =  0.87). Protection device related vascular complications, none of which led to neurologic symptoms, occurred after nine procedures (1.1%).

Your left carotid is more important than your right ▸ In 4006 right handed men and women > 65 years old followed for five years, after adjustment for right sided stenosis, high grade (⩾75% narrowing of diameter) stenosis of the left internal carotid artery (32 patients) was associated with cognitive impairment (odds ratio (OR) 6.7, 95% CI 2.4 to 18.1, compared with no stenosis) and cognitive decline (OR 2.6, 95% CI 1.1 to 6.3). Intima–media thickness of the left common carotid artery was associated with cognitive impairment and decline in univariate analysis, but this effect did not persist after adjustment. It remains to be seen if this is confirmed in other studies, but interest in asymptomatic carotid stenosis is growing.

## Journals scanned

American Journal of Medicine; American Journal of Physiology: Heart and Circulatory Physiology; Annals of Emergency Medicine; Annals of Thoracic Surgery; Archives of Internal Medicine; BMJ; Chest; European Journal of Cardiothoracic Surgery; Lancet; JAMA; Journal of Clinical Investigation; Journal of Diabetes and its Complications; Journal of Immunology; Journal of Thoracic and Cardiovascular Surgery; Nature Medicine; New England Journal of Medicine; Pharmacoeconomics; Thorax

## Reviewers

Dr Diana Gorog, Dr Akhil Kapur, Dr Masood Khan, Dr Alistair Lindsay; Dr Andrew Sharp

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