Clinical Impact

PCI 1 before & after (large)There are several areas where research carried out or led by Leicester, or where Leicester has made a major contribution as part of a multi-centre collaboration, has led to significant improvements in healthcare nationally, and internationally, as well as influenced clinical guidelines. Examples include the REACT trial showing the benefits of rescue angioplasty following failed thrombolysis for acute myocardial infarction (N Engl J Med 2005;353:2758-68), the UKPACE Study demonstrating that single chamber pacing for complete heart block in the elderly is as effective in terms of major outcomes as dual chamber pacing (N Engl J Med 2005;353:145-55), and the first randomised trial showing the clinical benefits of left atrial radiofrequency ablation during mitral valve surgery for continuous atrial fibrillation (JAMA 2005;294:2323-9). Significant contributions to studies such as ASCOT (Lancet 2005;366:895-906) and ADVANCE (Lancet 2007;370:829-40) have improved the management of hypertension. Leicester pioneered the clinical use of endovascular grafts for aortic aneurysm repair and was a major centre in the EVAR Trial, which defined their role in clinical practice (Lancet 2005;365:2179-86).

Control (left) and Drug Eluting Stent (right)Examples where our biomedical research has directly contributed to clinical benefit in the last 10 years include the development of drug-eluting stents, reduction of stroke risk during carotid endarterectomy (CEA) and the utility of plasma and urine measurements of natriuretic peptides (BNP and NTproBNP) in screening and exclusion of heart failure in the community. Percutaneous Coronary Intervention (PCI) with stenting has become a widely used technique for treatment of symptomatic coronary artery disease and in most countries now exceeds the use of coronary artery bypass surgery. The Achilles heel of PCI is restenosis from the healing response at the site of the vascular injury, requiring repeat intervention in 20-25% of patients. We were one of the first groups to provide proof of concept for the local delivery of therapeutic agents using vascular stents (Circulation 1996; 94:3311-7) to reduce restenosis and undertaken benchmark translational studies that have established the safety and efficacy of drug-eluting stents (DES) in humans (Circulation 2004;109:487-93). This and other collaborative studies (Lancet 2003; 362:1093-1099Circulation 2006; 113:1434-1441, N Engl J Med. 2009; 360:961-72) have established the place of DES in clinical practice and their endorsement in national and international guidelines. DES have reduced the need for a repeat procedure by approximately 10% absolute percentage points. In 2007, approximately 3 million DES were implanted worldwide which attest to their clinical value.

CEA is a proven procedure for preventing stroke, despite being responsible for causing a peri-operative stroke in 5-7% of patients. Post-operative stroke mainly follows embolisation of thrombus, accumulating on the cleaned inner surface of the artery in the first six hours. Using transcranial Doppler (TCD) ultrasound in the recovery area of theatre, our centre was the first to show that post-operative thrombotic stroke is preceded by a 1-2 hr phase of increasing microembolisation (J Vasc Surg 1994;20:104-7), and this is reduced dramatically by Dextran therapy (Eur J Vasc Endovasc Surg 1999;17:301-5). The combination of post-operative TCD monitoring with selective Dextran therapy in high risk patients (those showing increased microembolisation rates) has reduced the overall death/stroke rate in this centre (>1400 CEAs) by >60%. This reduction in risk has saved over £1 million in the costs of stroke rehabilitation over the last 10 years. However, post-op TCD monitoring is not a realistic option for all centres. In subsequent work, combining clinical and laboratory studies, we have shown that these high risk patients have platelets that are more sensitive to ADP (J Vasc Surg 2003;38:1226-31) and in a proof of principle trial found that in such patients this increased tendency is significantly reduced by pre-operative administration of 75mg of the ADP inhibitor clopidogrel (Circulation 2004;109:1476-81). Our current research is examining whether pre-operative administration of 75mg clopidogrel renders post-operative TCD monitoring unnecessary. If that were the case, it would be a very simple means of significantly reducing the risks of this procedure nationwide/internationally, while providing considerable savings in rehabilitation costs.

Diagnosis of heart failure, especially in the community is a challenge and often requires access to imaging by echocardiography for confirmation. In a proof of concept investigation funded by the NHS New and Emerging Applications of Technology programme, we demonstrated the utility of plasma and urine measurements of NTproBNP in screening and especially exclusion of heart failure in the community (JACC 2005;45:1043-50). NTproBNP is now used for exclusion of heart failure in general practice and in the emergency department as recommended in NICE guidelines (2010), guidelines from ESC/ACC/AHA (2009) and NIHR HTA 2009. A considerable benefit of wide application of this will be the reduction in inappropriate referrals for echocardiography, improving the usage of this scarcer and more expensive resource.

CAFE a sub-study of ASCOT led by Professor Bryan Williams showed that the different blood pressure lowering drugs can have different effects on central aortic pressures despite achieving similar brachial pressures and that this may be reflected in clinical outcomes (Circulation 2006; 113:1213-1225). In mechanistic studies, we have shown that heart rate is a key determinant of central aortic pressure in elderly hypertensives, an observation that has implications for the use of beta-blockers in this large patient group (J Am Coll Cardiol. 2009; 54:705-13). In other collaborative work we have contributed to the most detailed analysis of the relationship between on-treatment blood pressure in hypertensives and clinical outcomes (J Hypertens. 2009; 27:1360-9). This data is currently informing the revision of the NICE hypertension guidelines.

Our recent genetic findings are at an early stage of clinical application. However, even here some of the findings are identifying novel therapeutic possibilities. For example, we contributed to the initial demonstration that variants in the 5-lipo-oxygenase activating protein (FLAP) gene increase risk of myocardial infarction (Nat Genet 2004; 36:233-39). This has supported the possibility that leukotriene inhibition, already clinically used in the treatment of asthma, may prove beneficial in primary or secondary prevention of MI (JAMA 2005;293:2245-2256). Similarly, recent studies by ourselves (Am J Hum Genet 2008;82:139-49) and others have revealed that one of the novel loci affecting risk of CAD that we identified through our genome-wide analysis (New Engl J Med 2007;357:443-53) acts via a hitherto unknown pathway affecting plasma cholesterol level, identifying another potential therapeutic target. In collaborative work, using a Mendelian randomisation approach, we have shown that C-reactive protein, a biomarker associated with risk of coronary artery disease is probably not causal (JAMA. 2009; 302:37-48). This has important implications with regards to its suitability as a therapeutic target.

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