The Harmonising Outcomes with Revascularisation and Stents in Acute Myocardial Infarction (HORIZONS-AMI) was a prospective open label, multi-centre controlled trial involving patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). It incorporated two factorial randomised phases to allow a comparison of the direct thrombin inhibitor bivalirudin alone with heparin plus glycoprotein IIb-IIIa inhibitor use and a comparison of paclitaxel eluting stents (PES) with bare metal stents (BMS). Two primary clinical end-points were pre-specified: ischaemia driven TLR (analysis powered for superiority) and a composite safety end-point of major adverse cardiovascular events consisting of death, reinfarction, stroke and stent thrombosis (powered for non-inferiority with a 3.0% margin). The major secondary end-point was angiographic evidence of restenosis at 13 months

3602 patients with STEMI underwent randomisation for the pharmacological phase of the trial and of these 3006 underwent randomisation in a 3:1 ratio to the stent phase. 2257 were assigned to PES and 749 received BMS. 1 year follow up data were available for 2186 and 715 patients respectively. Patients with PES, when compared to those receiving BMS, had significantly lower ischaemia driven TLR (4.5% vs 7.5%, HR 0.59, 95%CI 0.43-0.83, p=0.002) and target vessel revascularisation (TVR) (5.8% vs 8.7%, HR 0.65, 95% CI 0.48-0.89, p=0.006), with non-inferior rates of the composite safety end-point (8.1% vs 8.0%, HR 1.02, 95%CI 0.76-1.36; absolute difference 0.1%, 95%CI -2.1 to 2.4, p=0.01 for non-inferiority, p=0.92 for superiority). Both PES and BMS had similar 12 month rates of death (3.5% and 3.5%, p=0.98) and stent thrombosis (3.2% and 3.4%, p=0.77) respectively. The 13 month rate of binary restenosis was significantly lower with PES than with BMS (10% vs 22.9%, HR 0.44, 95%CI 0.33-0.57, p<0.001).

There are some limitations of this study. Firstly, logistic complexities meant that an open label design was necessary. High rates of protocol compliance and the use of blinded clinical event adjudication and core laboratory assessments were measures taken to mitigate potential bias. There was a slightly higher rate of thienopyridine use in the PES arm than the BMS arm in the period between 6 months and 1 year. Very few patients with cardiogenic shock were included in this study and patients with unprotected left main stem disease or bifurcation disease requiring a 2 stent strategy were not included – therefore the results should not be extended to these patient populations. Longer term follow up data will be necessary to characterise the late safety and efficacy profiles of PES in patients with evolving STEMI particularly as the use of dual anti-platelet therapy declines over time after stent implantation. This is particularly important when considering the increased risk of stent thrombosis with DES when compared to BMSwhich may only become apparent at more than 1 year after stent implantation.

Conclusion:

The HORIZONS-AMI trial provides data indicating that PES may be used in patients with evolving STEMI. The data from HORIZONS-AMI show that approximately 30 fewer/1000 patients with PES required TVR at 1 year when compared to BMS.

· Stone GW, Lansky AJ, Pocock SJ et al. Paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction. The New England Journal of Medicine (2009) vol. 360 (19) pp. 1946-59

Despite a strong association between elevated blood glucose levels and increased rates of mortality among patients hospitalised with acute myocardial infarction (AMI), the benefit of acutely lowering levels of blood glucose remains controversial. Several questions remain unanswered:

(1) Does normalisation of admission hyperglycaemia improved outcome?

(2) What level of blood glucose is associated with lowest mortality?

(3) Do outcomes differ between patients who spontaneously achieve normalisation of glucose levels as compared to those who require insulin?

In order to address these questions Kosiborod et al retrospectively analyzed data from 7820 hyperglycaemic patients hospitalised for biomarker-confirmed AMI, using a database which received patient data from 40 hospitals across the US over a 6 year period (Jan 2000-Dec 2005). Measurements of blood glucose were divided into 5 levels as shown in the table below. Admission blood glucose level was defined as the initial blood glucose level, and postadmission blood glucose level was defined as the mean of all glucose levels obtained after the initial measurement. Patients with admission glucose levels <7.8 were excluded from the analysis. Outcome was defined as all cause in hospital mortality.

Patients with higher postadmission glucose levels had a higher incidence of heart failure (p<0.001) and diabetes (p<0.001) as compared to those with lower postadmission glucose levels. Furthermore these patients were less like to receive percutaneous intervention, had worse renal function, higher leukocyte count, were less frequently treated with antiplatelet drugs (including aspirin) and experienced longer hospital stays. Lower postadmission glucose levels were associated with better in hospital survival both in unadjusted and multivariate adjusted analyses (see table).

Lowest mortality was observed among patients with a postadmission glucose level of 4.4 – 7.2mmol/L. Interestingly, following multivariate adjustment admission glucose level failed to predict in hospital mortality (p=0.89) whereas postadmission glucose level remained a robust predictor (p<0.001). Propensity matching failed to demonstrate a difference in outcome among patients treated with insulin and those who were not.

Conclusion:

Glycaemic control, rather than insulin use, appears to be the important factor following AMI. However these results should be interpreted with caution as normalisation of glycaemia may simply represent a surrogate marker of healthy physiology and a recovery from the stress of AMI rather than identify a causal mechanism.

· Kosiborod M, Inzucchi S, Krumholz H et al. Glucose normalization and outcomes in patients with acute myocardial infarction. Arch Intern Med 2009;169(5):438-46

The ACTIVE Trial (Atrial Fibrillation Clopidogrel Trial with Irbesartan for the Prevention of Vascular Events) was designed to assess the role of clopidogrel and aspirin in the prevention of stroke and other vascular events in patients with atrial fibrillation (AF). ACTIVE W has already reported and compared clopidogrel + aspirin with a vitamin K antagonist. The ACTIVE A trial, the results of which are discussed here, compared combination therapy with clopidogrel and aspirin versus aspirin alone in patients with AF who were considered unsuitable for a Vitamin K antagonist.

This was a randomised, double-blind multi-centre trial involving 7554 patients from 580 centres in 33 countries. Patients were eligible for ACTIVE (either A or W) if they had AF at the time of enrolment or had had 2 episodes of AF in the preceding 6 months. Additionally, patients were required to have at least one of the following risk factors: age > 75 years, systemic hypertension, previous stroke or TIA, LVEF <45%, peripheral vascular disease or age 55-74 years and diabetes mellitus or coronary artery disease. Patients considered to be candidates for vitamin K antagonists were enrolled in ACTIVE W and those not considered suitable in ACTIVE A. Patients in both trials could also be randomised to ACTIVE I which involved factorial randomisation to either irbesartan or placebo – this study is ongoing.

Patients in ACTIVE A were randomised to either aspirin and clopidogrel (n=3772) or aspirin (n=3782). Follow up visits to assess compliance and clinical outcome were held at 1 month and then 3 monthly for the first year and 6 monthly until the end of the trial. The primary outcome was any major vascular event (stroke, non central nervous system systemic embolism, myocardial infarction or death from vascular causes). The main secondary outcome measures were the other individual components of the primary outcome and the composite of the primary outcome and major haemorrhage.

At a median of 3.6 years follow up, major vascular events had occurred in 832 patients receiving clopidogrel (6.8%/year) and 924 patients receiving placebo (7.6%/year), (relative risk with clopidogrel 0.89, 95%CI 0.81-0.98, p = 0.01). The difference was predominantly due to a reduction in the rate of stroke with clopidogrel – stroke occurred in 296 patients in the dual anti-platelet therapy arm (2.4%/year) versus 408 placebo patients (3.3%/year), (RR 0.72, 95%CI 0.62-0.83, p < 0.001). Myocardial infarction occurred in 90 patients receiving clopidogrel (0.7%/year) and 115 receiving placebo (0.9%/year, RR 0.78, 95%CI 0.59-1.03, p = 0.08). Major bleeding occurred in 251 patients receiving clopidogrel (2%/year) and 162 patients receiving placebo (1.3%/year) (RR1.57, 95%CI 1.29-1.92, p<0.001). Rates of discontinuation of the study medication were 16.3% and 15.2% for clopidogrel and placebo respectively at 1 year, rising to 39.4% and 37.1% at 4years. All patients were receiving aspirin at the time of randomisation and this decreased to 92.9% at 1 year and 81.1% at 4 years in both groups. A total of 777 patients (10.3%) received a vitamin K antagonist following discontinuation of the trial medication.

Conclusion:

For patients unable to take vitamin K antagonists, the addition of clopidogrel to aspirin therapy significantly reduced the rate of major vascular events, primarily driven by a reduction in strokes. However, one extra major bleeding episode would occur for ever 143 patients treated for one year with this combination.

· ACTIVE Investigators et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. The New England Journal of Medicine (2009) vol. 360 (20) pp. 2066-78

Animal studies have suggested that bone marrow cell injection can improve myocardial perfusion and improve ventricular function in chronic ischaemia, but the two randomized trials performed to date in humans have yielded conflicting results.

To investigate the effect of intramyocardial bone marrow cell injection on myocardial perfusion and left ventricular (LV) function further, Ramshorst et al. randomised 50 patients with chronic myocardial ischaemia to either intramyocardial injection of autologous bone marrow cells or placebo solution (25 patients per group). The primary outcome measure was myocardial perfusion as assessed by the summed stress score, a 17-segment score for stress myocardial perfusion assessed by Tc-99m tetrofosmin single-photon emission computed tomography (SPECT), while secondary measures included LV ejection fraction (LVEF) as assessed by MRI, Canadian Cardiovascular Society (CCS) angina class, and the Seattle Angina Questionnaire quality-of-life score.

After 3-months of follow-up, the summed stress score improved from 23.5 (SD, 4.7) to 20.1 (SD, 4.6; p<0.001) in the bone marrow cell group, compared with a decrease from 24.8 (SD, 5.5) to 23.7 (SD, 5.4; p=.004) in the placebo group. In those patients who underwent MRI, a 3% increase in LVEF was seen in the bone-marrow cell treated patients at 3 months (95% CI, 0.5% to 4.7%), but the placebo group showed no improvement. Improvements in CCS class an quality-of-life score were significantly greater in bone marrow cell-treated patients that in placebo-treated patients (p=.03 and p=.04, respectively).

Conclusion:

In this small study of patients with angina refractory to medical treatment, intramyocardial bone marrow injection resulted in a statistically significant improvement in myocardial perfusion, ejection fraction, and quality-of-life at 3 months. Whether this translates into an improvement in morbidity and mortality outcomes requires verification in further long-term studies.

· Van Ramshorst J, Bax JJ, Beeres SLMA et al. Intramyocardial bone marrow cell injection for chronic myocardial ischemia: a randomized controlled trial. JAMA (2009) vol. 301 (19) pp. 1997-2004