Pharmacological treatment for Type 2 diabetes integrating findings from cardiovascular outcome trials: an expert consensus in the UK.

In people with Type 2 diabetes, cardiovascular disease is a leading cause of morbidity and mortality. Thus, as well as controlling glucose, reducing the risk of cardiovascular events is a key goal. The results of cardiovascular outcome trials have led to updates for many national and international guidelines. England, Wales and Northern Ireland remain exceptions, with the most recent update to the National Institute for Health and Care Excellence (NICE) guidelines published in 2015. We reviewed current national and international guidelines and recommendations on the management of people with Type 2 diabetes. This article shares our consensus on clinical recommendations for the use of sodium-glucose co-transporter 2 inhibitors (SGLT-2is) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) in people with Type 2 diabetes and established or at very high risk of cardiovascular disease in the UK. We also consider cost-effectiveness for these therapies. We recommend considering each person's cardiovascular risk and using diabetes therapies with proven cardiovascular benefits when appropriate to improve long-term outcomes and cost-effectiveness.

Prediction of contrast induced acute kidney injury using novel biomarkers following contrast coronary angiography.

BACKGROUND/INTRODUCTION: Chronic kidney disease (CKD) is a risk factor for contrast induced acute kidney injury (CI-AKI). Contrast angiography in CKD patients is a common procedure. Creatinine is a delayed marker of CI-AKI and delays diagnosis which results in significant morbidity and mortality. AIM: Early diagnosis of CI-AKI requires validated novel biomarkers. DESIGN: A prospective observation study of 301 consecutive CKD patients undergoing coronary angiography was performed. METHODS: Samples for plasma neutrophil gelatinase-associated lipocalin (NGAL), serum liver fatty acid-binding protein (L-FABP), serum kidney injury marker 1, serum interleukin 18 and serum creatinine were taken at 0, 1, 2, 4, 6 and 48 h post-contrast. Urinary NGAL and urinary cystatin C were collected at 0, 6 and 48 h. Incidence of major adverse clinical events (MACE) was recorded at 1 year. CI-AKI was defined as an absolute delta rise in creatinine of ≥26.5 µmol/l or a 50% relative rise from baseline at 48 h following contrast. RESULTS: CI-AKI occurred in 28 (9.3%) patients. Plasma NGAL was most predictive of CI-AKI at 6 h. L-FABP performed best at 4 h. A combination of Mehran score > 10, 4 h L-FABP and 6 h NGAL improved specificity to 96.7%. MACE was statistically higher at 1 year in CI-AKI patients (25.0 vs. 6.2% in non-CI-AKI patients). DISCUSSION/CONCLUSION: Mehran risk score, 4 h serum L-FAPB and 6 h plasma NGAL performed best at early CI-AKI prediction. CI-AKI patients were four times more likely to develop MACE and had a trebling of mortality risk at 1 year.

Heart-type fatty acid-binding protein (H-FABP) and highly sensitive troponin T (hsTnT) as markers of myocardial injury and cardiovascular events in elective percutaneous coronary intervention (PCI).

BACKGROUND/INTRODUCTION: Type 4a myocardial infarction (MI) occurs when myocardial injury is combined with either symptoms suggestive of myocardial ischaemia, new left bundle branch block, angiographic loss of patency of a major artery or imaging suggestive of new loss of myocardium. Myocardial injury is defined as a rise of >5 x 99th upper reference limit (URL) of 14 ng/l (i.e. >70 ng/l) for highly sensitive troponin T (hsTnT) at 6 h if hsTnT was normal at baseline or >20% rise from 0 to 6 h if hsTnT was >14 ng/l at baseline. AIM: To assess the prognostic value of biomarkers of myocardial injury following elective percutaneous coronary intervention (PCI). DESIGN: A cohort of 209 patients were included of whom 144 (68.9%) were male, mean age was 68.8 years, 28 (13.4%) were smokers, 31 (14.8%) were diabetic, 199 (95.2%) had hypercholesterolaemia and 138 (66.0%) had hypertension. METHODS: We evaluated hsTnT, heart-type fatty acid-binding protein (H-FABP), troponin I (TnI), creatine kinase MB type (CKMB), myoglobin, glycogen phosphorylase BB (GPBB) and carbonic anhydrase III (CA III) at 0, 4, 6 and 24 h following elective PCI. Patients were followed up at 1 year to assess for major adverse clinical events (MACE). RESULTS: Myocardial injury was observed in 37 (17.7%) patients. Median hsTnT/H-FABP at 4 h were most predictive. MACE was noted in 6 (2.9%) patients, 3 had type 4a MI post PCI, P = 0.036. DISCUSSION/CONCLUSIONS: Median 4 h hsTnT/H-FABP were most predictive of myocardial injury following PCI. H-FABP and hsTnT were predictive of MACE.

Contemporary management of coronary heart disease.

Coronary heart disease remains the leading cause of mortality in the UK. This review focuses on the contemporary management of patients with acute coronary syndromes and those with stable angina, including the role of primary percutaneous coronary intervention versus fibrinolytic therapy in a UK setting, current and emerging antiplatelet and anticoagulant therapies and the latest guidance on secondary prevention/lifestyle modification.

A timely diagnosis of myocardial infarction.

The diagnosis of acute myocardial infarction currently rests on the measurement of troponin, a biomarker of myocardial necrosis. Unfortunately, the current generation troponin assays detect troponin only 6-9 h after symptom onset. This can lead to a delay in diagnosis and also excessive resource utilization when triaging patients who, ultimately, have noncardiac causes of acute chest pain. For these reasons, there has been extensive research interest in biomarkers that can detect and rule out myocardial infarction early after symptom onset. These include markers of myocardial injury, such as myoglobin, heart-type fatty acid binding protein, glycogen phosphorylase BB; hemostatic markers, such as D-dimer; and finally, inflammatory markers, such as matrix metalloproteinase 9. Recently, highly sensitive troponin assays have reported an early sensitivity for myocardial infarction of greater than 95%, although at a cost of reduced specificity. The optimal strategy with which to use these novel biomarkers and highly sensitive troponins has yet to be determined, and interpretation of their results in light of thorough clinical assessment remains essential.

Is there a Failure to Optimize theRapy in anGina pEcToris (FORGET) study?

BACKGROUND: In the management of chronic stable angina, percutaneous coronary intervention (PCI) provides symptomatic relief of angina rather than improvement of prognosis. Current guidelines recommend optimization of medical therapy prior to elective PCI. It is not clear if these guidelines are adhered to in clinical practice. AIM: The aim of this multi-centre study was to determine the extent to which these treatment guidelines are being implemented in the UK. DESIGN: This was a multi-centre study involving six hospitals in the UK. METHODS: The medical treatment and extent of risk factor modification was recorded for consecutive patients undergoing elective PCI for chronic stable angina at each site. Data collected included anti-anginal drug therapy, lipid levels and blood pressure (BP). Data on heart rate (HR) control were also collected, since this represents a fundamental part of medical anti-anginal therapy. Target HR is <60 b.p.m. for symptomatic angina. RESULTS: A total of 500 patients [74% male; mean age +/- SD (64.4 +/- 10.1 years)] were included. When considering secondary prevention, 85% were receiving a statin and 76% were on an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. In terms of medical anti-ischaemic therapy, 78% were receiving beta-blockers [mean equivalent dose of bisoprolol 3.1 mg (range 1.25-20 mg)], 11% a rate limiting calcium antagonist, 35% a nitrate or nicorandil and one patient was receiving ivabradine. The mean total cholesterol (95% confidence interval) was 4.3 mmol/l (4.2-4.4), mean systolic BP of 130 +/- 24 mmHg and mean diastolic BP of 69 +/- 13 mmHg. Serum cholesterol was <5 mmol/l in 77% and <4 mmol/l in 42% of the patients, 62% of the patients had systolic BP < 140 mmHg and 92% had diastolic BP < 90 mmHg. Considering European Society of Cardiology targets, 50% had systolic BP < 130 mmHg and 76% had diastolic BP < 80 mmHg. A large proportion of patients did not achieve target resting HR; 27% of patients had a resting HR of >or=70 b.p.m., 40% had a resting HR between 60 and 69 b.p.m. and 26% had a resting HR between 50 and 59 b.p.m. The resting HR was not related to the dose of beta-blocker. CONCLUSION: A significant proportion of the patients with chronic stable angina undergoing elective PCI did not achieve therapeutic targets for lipid, BP and HR control. Over 50% of patients did not receive adequate HR lowering anti-anginal therapy to achieve recommended target resting HR.

Dyslipidemia therapy update: the importance of full lipid profile assessment.

Lipid guidelines typically focus on total cholesterol +/- low-density lipoprotein cholesterol levels with less emphasis on high-density lipoprotein cholesterol (HDL-C) or triglyceride assessment, thus potentially underestimating cardiovascular (CV) risk and the need for lifestyle or treatment optimization. In this article, we highlight how reliance on isolated total cholesterol assessment may miss prognostically relevant lipid abnormalities; we describe from the European Systematic COronary Risk Evaluation (SCORE) data set how incorporation of HDL-C may improve estimation of CV risk; and, finally, we critically evaluate the evidence base surrounding triglycerides and CV risk.

Investigation of a multimarker approach to the initial assessment of patients with acute chest pain.

Early identification of acute coronary syndrome (ACS) is important to guide therapy at a time when it is most likely to be of value. In addition, predicting future risk helps identify those most likely to benefit from ongoing therapy. Cardiac troponin T (cTnT) is useful for both purposes although cannot reliably rule out ACS until 12 hours after pain onset and does not fully define future risk. In this review article we summarize our previously published research, which assessed the value of myocyte injury, vascular inflammation, hemostatic, and neurohormonal markers in the early diagnosis of ACS and risk stratification of patients with ACS. In addition to cTnT, we measured heart fatty acid binding protein (H-FABP), glycogen phosphorylase-BB, high-sensitivity C-reactive protein, myeloperoxidase, matrix metalloproteinase 9, pregnancy-associated plasma protein-A, D-dimer, soluble CD40 ligand, and N-terminal pro-brain natriuretic peptide (NT-proBNP). Of the 664 patients enrolled, 415 met inclusion criteria for the early diagnosis of acute myocardial infarction (MI) analysis; 555 were included in the risk stratification analysis and were followed for 1 year from admission. In patients presenting <4 hours from pain onset, initial H-FABP had higher sensitivity for acute MI than cTnT (73% vs. 55%; P=0.043) but was of no benefit beyond 4 hours when compared to cTnT. On multivariate analysis, H-FABP, NT-proBNP, and peak cTnT were independent predictors of 1-year death/MI. Our research demonstrated that, in patients presenting within 4 hours from pain onset, H-FABP may improve detection of ACS. Measuring H-FABP and proBNP may help improve long-term risk stratification.

Body surface mapping improves early diagnosis of acute myocardial infarction in patients with chest pain and left bundle branch block.

OBJECTIVE: To test prospectively depolarisation and repolarisation body surface maps (BSMs) for mirror image reversal, which is less susceptible to artefact, in patients with acute ischaemic-type chest pain, and to compare these BSM criteria with previously published 12 lead ECG criteria. METHODS: An 80 lead portable BSM system was used to map patients presenting with acute ischaemic-type chest pain and a 12 lead ECG with left bundle branch block (LBBB). Acute myocardial infarction (AMI) was defined by serial cardiac enzymes. Each 12 lead ECG was assessed by the criteria of Sgarbossa et al and Hands et al for diagnosis of AMI. Depolarisation and repolarisation BSMs were assessed for loss of mirror image reversal of QRS with ST-T isointegral map patterns and a change in vector angle from QRS to ST-T outside 180+/-15 degrees -findings typically seen in LBBB with AMI. RESULTS: Of 56 patients with chest pain and LBBB, 18 had enzymatically confirmed AMI. Patients with loss of BSM image reversal were significantly more likely to have AMI (odds ratio 4.9, 95% confidence interval 1.5 to 16.4, p = 0.007). Loss of BSM image reversal was significantly more sensitive (67%) for AMI than either 12 lead ECG method (17%, 33%) albeit with some loss in specificity (BSM 71%, 12 lead ECG 87%, 97%). Patients with AMI compared with those without AMI had a greater mean change in vector angle outside the normal range (180+/-15 degrees ), particularly between QRS isointegral and ST60 isopotential (the potential 60 ms after the J point at each electrode site) BSMs (19 degrees v 9 degrees, p = 0.038). Loss of image reversal and QRS-ST60 vector change outside 180+/-15 degrees had 61% sensitivity and 82% specificity for AMI (odds ratio 7.0, 95% confidence interval 2.0 to 24.4, p = 0.001). CONCLUSIONS: BSM compared with the 12 lead ECG improved the early diagnosis of AMI in the presence of LBBB.

Impact of pre-hospital care in patients with acute myocardial infarction compared with those first managed in-hospital.

AIMS: To compare prospectively the impact of pre-hospital care by a physician-staffed mobile coronary care unit with patients managed initially in-hospital, all with acute myocardial infarction. METHODS AND RESULTS: This was a single centre registry of consecutive patients (n=750) admitted with acute myocardial infarction to the coronary care unit and cardiology wards of the Royal Victoria Hospital, Belfast between 1998 and 2001. For the 750 patients, in-hospital mortality was 11% and was significantly lower for those managed pre-hospital (8% vs 13%, P=0.04): patients who received fibrinolytic therapy (n=474), the in-hospital mortality was significantly lower in the pre-hospital group (7% vs 13%, P=0.02). Those managed pre-hospital had significant reduction in the median delay times (25th, 75th percentiles) from onset of symptoms to call for help 1.0 (0.5, 2.2) vs 2.0 (0.9, 6.0) h, P<0.001, from call for help to receiving fibrinolytic therapy 1.0 (0.8, 1.5) vs 1.8 (1.2, 2.5) h, P<0.001 resulting in a shorter pain-to-needle time for fibrinolytic therapy 2.3 (1.5, 3.8) vs 4.0 (2.6, 7.2) h, P<0.001. For all patients, older age, haemodynamic indicators on admission (hypotension, higher heart rate, heart failure) and managed by the in-hospital route were significant independent variables for an adverse in-hospital mortality. Although for patients aged >or=75 years no statistical significant reduction in mortality occurred for those managed pre-hospital (P=0.051), nevertheless patients in this age group first treated pre-hospital who received fibrinolytic therapy had a significantly lower mortality than those first treated in-hospital (21% vs 43%, P=0.02). CONCLUSIONS: Consecutive patients with acute myocardial infarction seen and managed initially out-of-hospital by a physician-staffed mobile coronary care unit had significantly lower in-hospital mortality.

Randomized comparison of enoxaparin with unfractionated heparin following fibrinolytic therapy for acute myocardial infarction.

AIMS: To compare the efficacy and safety of low molecular weight heparin with unfractionated heparin following fibrinolytic therapy for acute myocardial infarction. METHODS AND RESULTS: Three-hundred patients receiving fibrinolytic therapy following acute myocardial infarction were randomly assigned to low molecular weight heparin as enoxaparin (40 mg intravenous bolus, then 40 mg subcutaneously every 8 h, n=149) or unfractionated heparin (5000 U intravenous bolus, then 30 000 U. 24 h(-1), adjusted to an activated partial thromboplastin time 2-2.5x normal, n=151) for 4 days in conjunction with routine therapy. Clinical and therapeutic variables were analysed, in addition to use of enoxaparin or unfractionated heparin, to determine independent predictors of the 90-day composite triple end-point (death, non-fatal reinfarction, or readmission with unstable angina). The triple end-point occurred more frequently in patients receiving unfractionated heparin rather than enoxaparin (36% vs. 26%; P=0.04). Logistic regression modelling of baseline and clinical variables identified the only independent risk factors for recurrent events as left ventricular failure, hypertension, and use of unfractionated heparin rather than enoxaparin. There was no difference in major haemorrhage between those receiving enoxaparin (3%) and unfractionated heparin (4%). CONCLUSION: Use of enoxaparin compared with unfractionated heparin in patients receiving fibrinolytic therapy for acute myocardial infarction was associated with fewer recurrent cardiac events at 90 days. This benefit was independent of other important clinical and therapeutic factors.

Suspected angina pectoris: a rapid-access chest pain clinic.

We prospectively evaluated a rapid-access chest pain clinic in terms of clinical diagnoses, outcomes, morbidity and mortality at 3 months follow-up in patients, and cost-effectiveness. All patients seen at the clinic from February 1999 to December 2000 were assessed. Referring doctors indicated the management they would have provided had the clinic been unavailable, to allow a cost-effectiveness analysis. Overall, 709 patients were referred, 471 (66%) from General Practitioners, 212 (30%) from Accident and Emergency doctors and 26 (4%) from other sources. All had recent onset, or increasing frequency of ischaemic-type chest pain (excluding those with suspected myocardial infarction or rest chest pain angina). Fifty-one (7%) had acute coronary syndromes, 119 (17%) had stable ischaemic heart disease, 144 (20%) had possible ischaemic heart disease, and 395 (56%) were considered to have non-ischaemic symptoms. Some 70% of patients were seen within 24 h. Only 57 patients (8%) were admitted. Had the clinic been unavailable, 160 patients would have been admitted. Out-patient cardiology appointments were arranged for 116 patients (16%), and 429 patients (60%) were discharged directly. Follow-up data at 3 months were obtained from 565/567 eligible patients (99.6%). No major cardiac events (death/myocardial infarction) occurred in those with non-ischaemic chest pain. There were five deaths (including one due to cancer) and three patients had a myocardial infarction (event rate 1%). There were eleven readmissions for angina: six were in patients with acute coronary syndromes, and four of these six were awaiting revascularization. The estimated net saving was pound 58/patient. A rapid-access chest pain clinic offers a prompt, safe and cost-effective service in a challenging group of patients.

ST depression only on the initial 12-lead ECG: early diagnosis of acute myocardial infarction.

AIMS: To compare the diagnostic ability of the 12-lead ECG with body surface mapping for early detection of acute myocardial infarction in patients presenting with ST depression only on the 12-lead ECG. METHODS AND RESULTS: Fifty-four consecutive patients with chest pain <24 h and ST depression were recruited. A 12-lead ECG and 80-lead body surface map were recorded at presentation from which univariate and multivariate prediction models of acute myocardial infarction were developed. Patients were randomly divided into a training-set and a validation-set. Acute myocardial infarction occurred in 16/30 training-set and 8/24 validation-set patients. Univariate prediction of acute myocardial infarction by the 12-lead ECG, based on the depth or numbers of leads with ST depression, was not improved by assessment of ST elevation outside the conventional 12 leads using body surface mapping. The optimum multivariate 12-lead ECG model developed in training-set patients (six ST depression variables) had poor sensitivity (38%) although good specificity (81%) for acute myocardial infarction when tested prospectively in validation-set patients. In contrast, the optimum body surface mapping model developed in training-set patients (three isointegral or isopotential variables) achieved high sensitivity (88%) whilst maintaining good specificity (75%) for acute myocardial infarction when tested prospectively in validation-set patients. CONCLUSION: Body surface mapping, when compared with the 12-lead ECG, may improve the early diagnosis of acute myocardial infarction in patients presenting with chest pain and ST depression only on the 12-lead ECG.

Combination reperfusion therapy with abciximab and reduced dose reteplase: results from TIMI 14. The Thrombolysis in Myocardial Infarction (TIMI) 14 Investigators.

Aims Abciximab has previously been shown to enhance thrombolysis and improve myocardial perfusion when combined with reduced doses of alteplase. The purpose of the reteplase phase of TIMI 14 was to evaluate the effects of abciximab when used in combination with a reduced dose of reteplase for ST-elevation myocardial infarction. Methods and Results Patients (n=299) with ST-elevation myocardial infarction were treated with aspirin and randomized to a control arm with standard dose reteplase (10+10 U given 30 min apart) or abciximab (bolus of 0.25 mg. kg(-1)and 12-h infusion of 0.125 microg. kg(-1). min(-1)) in combination with reduced doses of reteplase (5+5 U or 10+5 U). Control patients received standard weight-adjusted heparin (bolus of 70 U. kg(-1); infusion of 15 U. kg(-1). h(-1)), while each of the combination arms with abciximab and reduced dose reteplase received either low dose heparin (bolus of 60 U. kg(-1); infusion of 7 U. kg(-1). h(-1)) or very low dose heparin (bolus of 30 U. kg(-1); infusion of 4 U. kg(-1). h(-1)). The rate of TIMI 3 flow at 90 min was 70% for patients treated with 10+10 U of reteplase alone (n=87), 73% for those treated with 5+5 U of reteplase with abciximab (n=88), and 77% for those treated with 10+5 U of reteplase with abciximab (n=75). Complete (>/=70%) ST resolution at 90 min was seen in 56% of patients receiving a reduced dose of reteplase in combination with abciximab compared with 48% of patients receiving reteplase alone. Conclusions Reduced doses of reteplase when administered in combination with abciximab were associated with higher TIMI 3 flow rates than reported previously for reduced doses of reteplase without abciximab and were at least as high as for full dose reteplase alone