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ACUITY at 1 year

The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial showed that in patients with moderate- and high-risk acute coronary syndromes undergoing early invasive treatment, bivalirudin monotherapy gave non-inferior rates of adverse ischaemic events and decreased rates of major bleeding when compared with heparin plus glycoprotein IIb/IIIa (GP IIb/IIIa) inhibition. ACUITY enrolled 13 819 patients from 450 academic and community-based institutions in 17 countries. Patients were assigned to receive either heparin plus GP IIb/IIIa inhibitors (n = 4603), bivalirudin plus GP IIb/IIIa inhibitors (n = 4604), or bivalirudin monotherapy (n = 4612). Of these patients, 4605 were assigned to routine upstream administration of GP IIb/IIIa inhibitors, and 4602 were deferred to selective administration. The main outcome measure was a composite of death, myocardial infarction, or unplanned revascularisation for ischaemia at 1 year.

At 1 year, 15.4% of patients given heparin plus GP IIb/IIIa inhibitors had one of the composite ischaemic end points, compared with 16.0% of those assigned to bivalirudin plus GPIIb/IIIa inhibitors (p = 0.35) and 16.2% assigned to bivalirudin monotherapy (p = 0.29). Mortality rates in the same treatment groups were 3.9%, 3.9% and 3.8%, respectively. Composite ischaemia occurred in 16.3% of patients assigned to deferred use compared with 15.2% of patients assigned to upstream administration (p = 0.15).

Although not statistically significant, the trend towards lower mortality at 1 year is reassuring given the numerically higher 30-day event rate in the original trial. Bleeding at 30 days was a significant predictor of mortality, therefore the reduced rates in the bivalirudin group may have levelled the mortality outcomes at 1 year. Combined with the recent HORIZONS trial, which showed a reduction in mortality at 30 days in patients with ST-elevation acute coronary syndrome receiving bivalirudin, it now at least appears to be a serious alternative to heparin and GP II6/IIIa inhibitors.

Stone GW, Ware JH, Bertrand ME. Antithrombotic strategies in patients with acute coronary syndromes undergoing early invasive management. One-year results from the ACUITY trial. JAMA 2007;298:2497–506.

1 in 10 Primary PCI calls unnecessary

Rapid reperfusion is associated with improved outcomes in patients presenting with ST-elevation acute coronary syndromes (STE-ACS). However, ACS are not the only cause of ST-elevation and misdiagnosis may have a number of clinical and financial consequences, among them a “false-positive” activation of the cardiac catheterisation laboratory team. Larson et al used a prospective registry to determine the prevalence, aetiology, and outcomes of false-positive cases of cardiac catheterisation laboratory activation.

Between March 2003 and November 2006, 1345 patients presented to, or were transferred to, the Minneapolis Heart Institute with a suspected STE-ACS. In this system, an emergency department doctor made a single telephone call to activate the cardiac catheterisation laboratory, but in cases of diagnostic uncertainty the ECG was first faxed to an attending cardiologist for review (although 24-hour cardiology cover was only available at the tertiary centre). Of the 1335 patients who underwent angiography, 187 (14%) had no culprit coronary artery and 127 (9.5%) did not have significant coronary artery disease. Cardiac biomarkers were negative in 11.2%, and 9.2% of patients had neither a biomarker rise nor an obvious culprit coronary artery. At 30 days, mortality in those with a culprit coronary artery was 4.6%, compared with 2.7% in those without.

These figures show that unnecessary cardiac catheterisation laboratory activation is a relatively common phenomenon in clinical practice; between 9–14% of cases depending on the definition of false positive used. Although it is inevitable that not all cases will be clear cut, it is important that individual hospitals know their own rate of false-positive results to ensure the correct balance is maintained between genuine emergencies, and those cases that may first benefit from further diagnostic tests. This is particularly important as a mortality rate of 2.7% in those who were “false positive” suggests that this group need further attention—they are not “normal”.

Larson DM, Menssen KM, Sharkey SW, . “False-positive” cardiac catheterization laboratory activation among patients with suspected ST-segment elevation myocardial infarction. JAMA 2007;298:2754–60.


Avandia: further evidence of increased cardiovascular risk

The use of the thiazolidinediones, rosiglitazone and pioglitazone, is associated with weight gain, oedema and an increased risk of congestive heart failure. Furthermore, two recent meta-analyses suggested that rosiglitazone (Avandia) might be associated with an increased risk of acute myocardial infarction and death.

Lipscombe et al performed a population-based, retrospective, cohort study that was analysed using a nested case–control approach. Health databases from Ontario, Canada were searched to find diabetic patients aged 66 years or older treated with at least one oral hypoglycaemic agent between 2002 and 2006 (n = 159 026), all of whom were followed up until March 2006. The primary outcome studied was an emergency visit to hospital with congestive heart failure, while the secondary outcomes were an emergency department visit or admission to hospital for acute myocardial infarction, and all cause mortality.

The median follow-up period was 3.8 years, 12 491 patients (7.9%) had a hospital visit for congestive heart failure, 12 578 (7.9%) had a visit for acute myocardial infarction, and 30 265 (19%) died. Current treatment with a thiazolidinedione was associated with a significantly increased risk of congestive heart failure (adjusted rate ratio 1.6), acute myocardial infarction (adjusted rate ratio 1.4), and death (adjusted rate ratio 1.29), compared with other oral hypoglycaemic combination treatments. However, the increased risk of congestive heart failure, acute myocardial infarction, and mortality associated with thiazolidinedione use was limited to rosiglitazone.

Those aged over 65 have the highest prevalence of diabetes, but the majority of clinical trials looked at those aged 65 years and younger. Although this is an observational study and does not contain randomised data, it is now the fourth meta-analysis to show an increased cardiovascular risk with rosiglitazone. The current labelling of thiazolidinediones warns against use only in people at high risk of congestive heart failure—pressure now rests on the FDA to take more definitive action on the use of Avandia.

Lipscombe LL, Gomes T, Lévesque LE, . Thiazolidinediones and cardiovascular outcomes in older patients with diabetes. JAMA 2007;298:2634–43.

Patent foramen ovale and cryptogenic stroke

Prevalence of patent foramen ovale (PFO) decreases with increasing age, yet most previous studies have examined the risk of stroke in younger patients with PFO. The objective of this single-centre study was to clarify the relationship in patients >55 years of age and to compare this with younger patients.

Five hundred and ninety-six consecutive patients with stroke, aged between 18 and 85 years, were enrolled; data from 503 were analysed as many were unable to undergo transoesophageal echocardiography. The TOAST (Trial of Org 10 172 in Acute Stroke Treatment) criteria were used to classify the cause of infarction before transoesophageal echocardiography. These subdivide the cause of stroke into five subtypes based on clinical features and the results of diagnostic testing: large artery atherosclerosis, cardioembolism, small vessel occlusion, stroke of other known cause and stroke of unknown cause.

The prevalence of PFO was significantly greater among patients with cryptogenic stroke than among those with stroke of known cause in both the younger patients (43.9% vs 14.3%, odds ratio (OR) = 4.70, 95% CI 1.89 to 11.68, p<0.001) and older patients (28.3% vs 11.9%, OR = 2.92, 95% CI 1.70 to 5.01, p<0.001). There was a significant association between the presence of PFO with concomitant atrial septal aneurysm and cryptogenic stroke, as compared with stroke of known cause among both younger patients (13.4% vs 2.0%, OR = 7.36, 95% CI 1.01 to 326.0, p = 0.049) and older patients (15.2% vs 4.4%, OR = 3.88, 95% CI 1.78 to 8.46, p<0.001). Multivariate analyses with adjustment for age, plaque thickness, presence/absence of coronary artery disease and hypertension, demonstrated that PFO was independently associated with stroke in both the younger (OR = 3.70, 95% CI 1.42 to 9.65, p = 0.008) and the older group (OR = 3.00, 95% CI 1.73 to 5.23, p<0.001).

Previous studies in patients with PFO have been limited by selection bias as older patients tended to undergo transoesophageal echocardiography less frequently than younger patients. The question of a causal relationship between PFO and stroke is difficult to answer in the older population as they often have other sources of embolus such as atherosclerotic disease. In this regard, it is important to note that in this study older patients with PFO and cryptogenic stroke had significantly less severe atherosclerosis than those without PFO.

Several randomised controlled trials are underway which may clarify the benefits of percutaneous closure versus medical treatment. However, all the current studies include patients of <60 years on enrolment—further studies including older age groups will be necessary to develop appropriate management strategies for this group of patients.

Handke M, Harloff A, Olschewski M. Patent foramen ovale and cryptogenic stroke in older patients. N Engl J Med 2007;357:2262–8.

The childhood obesity epidemic and coronary artery disease risk

The childhood obesity epidemic continues to grow at an alarming rate world wide. It has been demonstrated that overweight children already have risk factors for coronary heart disease (CHD) such as dyslipidaemia, hypertension, impaired glucose tolerance and vascular abnormalities. The New England Journal of Medicine devotes two important articles to this topic.

The first report is a cohort study of 276 835 Danish schoolchildren in Copenhagen (born from 1930 to 1976) for whom recorded measurements of weight and height were available. The authors calculated each child’s body mass index (BMI) and, from data recorded from health examinations between 1955 and 1960, created internal age- and sex-specific BMI references. Information with respect to CHD events was obtained by linking health records to the National Cause of Death Register and the National Hospital Discharge Register. CHD events were classified as non-fatal or fatal. Follow-up of subjects began at 25 years of age or in 1977 (when the National Hospital Discharge Register was established) whichever came later. Follow-up from 25 years of age was chosen as the earliest age to assess adult outcomes since CHD events at a younger age tend to be a reflection of either congenital defects or cardiac arrhythmias.

In 5 063 622 person-years of follow-up, 10 235 men and 4318 women for whom childhood BMI data were available received a diagnosis of CHD or died of CHD as adults. The risk of any CHD event, a non-fatal event and a fatal event among adults was positively associated with BMI at 7–13 years of age for boys and 10–13 years of age for girls. Associations were linear for age and the risk increased across the whole BMI distribution. Additionally, risk increased as the age of the child increased, and adjusting for weight strengthened the results.

At the present time, children are classified as being at risk only if their BMI values are above the 85th centile on growth charts. However, the data from this study do not support this: the linearity of the association demonstrated implies that even a small amount of weight gain will increase the risk of CHD. This research suggests that intervention should be targeted at helping children to achieve and maintain appropriate weight early in order to prevent further deleterious health consequences.

A second paper used the CHD Policy Model (a computer simulation) of the incidence, prevalence, mortality and costs associated with CHD in US residents aged <35 years to estimate the potential effect of overweight adolescents on future adult CHD. An overweight adolescent was defined as having a weight >95th centile on growth charts and an obese adult a BMI >30.

The current number of obese adolescents is projected to increase the prevalence of obese 35- year olds in 2020 to a range of 30–37% in men and 34–44% in women. The consequence of this increased obesity will be an increase in the incidence of CHD and the total number of CHD events and deaths projected to occur into early adulthood and middle age. By 2035 the prevalence of CHD is estimated to increase by 5–16%, with >100 000 excess cases of CHD attributable to increased obesity. Prompt, aggressive treatment with the current therapeutic modalities to modify reversible risk factors would reduce but would not eliminate this projected increase.

Aggressive treatment of hypertension and dyslipidaemia in young adulthood will be required to decrease the risk of CHD that is associated with obesity, and additional measures will be required to deal with the obesity related risk of diabetes. It is sobering to think that many of the modelling assumptions used may actually lead to an underestimation as obesity is on the rise in adults as well as adolescents.

Baker JL, Olsen LW, Sorensen TIA. Childhood body-mass index and the risk of coronary heart disease in adulthood. N Engl J Med 2007;357:2329–37.

Bibbins-Domingo K, Coxson P, Pletcher MJ, . Adolescent overweight and future adult coronary heart disease. N Engl J Med 2007;357:2371–9.


Coupling protein could improve cardiac cell transplantation

Results to date of cell transplantation for heart failure secondary to ischaemic heart disease have shown only modest improvements in cardiac function, perhaps owing to the fact that neither skeletal myoblasts or bone marrow cells adopt a fully cardiac phenotype or are capable of coupling electrically with the host myocardium.

Roell et al examined the ability of four different types of mouse cell to integrate into myocardium following myocardial infarction: embryonic cardiomyocytes (eCMs), skeletal myoblasts, bone marrow cells and cardiac myofibroblasts. Only eCMs protected against the induction of ventricular tachycardia and this was found to be due to improved electrical coupling between these cells and the surrounding myocardium. However, skeletal myoblasts genetically engineered to express the gap junction protein connexin 43, which is present in heart-muscle but not skeletal-muscle cells, became able to protect against ventricular tachycardia to a similar extent as eCMs.

The results suggest a key role for connexin 43 in electrical coupling in the heart, and offer the possibility that human skeletal muscle cells might be made to better integrate into damaged myocardium if the gene for connexin 43 were to be inserted ex vivo. But human and mice hearts differ significantly and a large animal model is the next step for this new and exciting piece of research.

Roell W, Lewalter T, Sasse P, . Engraftment of connexin 43-expressing cells prevents post-infarct arrhythmia. Nature 2007;450:819–26.

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; JAMA; Journal of Clinical Investigation; Journal of Diabetes and its Complications; Journal of Immunology; Journal of Thoracic and Cardiovascular Surgery; Lancet; Nature Medicine; New England Journal of Medicine; Pharmacoeconomics; Thorax


Dr Alistair C Lindsay, Dr Katie Qureshi