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Randomised placebo-controlled trials (RCTs) are the most robust way to demonstrate the effectiveness of medical therapies. The University of Glasgow's Robertson Centre for Biostatistics (RCB) is internationally renowned for its biostatistical input and leading roles on landmark RCTs of cardiovascular therapies. The findings of the BEAUTIFUL and SHIFT studies underpinned European and UK regulatory approval for a novel use of the heart-rate-lowering drug ivabradine, potentially preventing thousands of hospital admissions for heart failure every year. The IONA trial supported UK approval of generic versions of another heart drug (nicorandil), thereby enhancing cost-effectiveness for the NHS. The BEAUTIFUL, SHIFT, DOT-HF and CAPRICORN trials provided the evidence base for US, European and UK guideline recommendations, steering best practice for treatment of patients with heart disease worldwide.
Impact: Health and welfare, policy and clinical practice; randomised trial evidence has changed the management and outcome of acute coronary syndromes (ACS) globally.
Significance: Advanced anti-platelet and revascularisation therapies have become standards of care worldwide. There have been large (10-50%) reductions in the death rate from coronary heart disease across Europe. Clopidogrel was the second best-selling drug in the USA in 2011.
Beneficiaries: Patients with ACS, clinical practitioners, NHS and healthcare delivery organisations, policy-makers, pharmaceutical companies.
Attribution: Building on prior studies, Fox (UoE) and colleagues led multicentre randomised controlled trials; international trials were co-chaired by Fox with international investigators.
Reach: Global; guideline changes in Europe and USA; applies to the up to 5% of the population who have ACS.
Research at UCL firmly established tacrolimus as the optimal calcineurin inhibitor to use in immunosuppressive regimens following liver transplantation. Compared to ciclosporin its use improved graft survival by 6% and patient survival by 7%. Assuming 550 liver transplants per year in the UK since 2008, we can estimate that, with 90% of patients treated with tacrolimus and 10% ciclosporin, tacrolimus-based immunosuppression has resulted in 165 grafts and 192 lives being saved during the period 2008-13.
The Acute Infarct Ramipril Efficacy (AIRE) multicentre international trial, conceived, designed, led and coordinated by Leeds was the first to show that use of early angiotensin converting enzyme Inhibitor (ACEI) therapy in patients with signs and symptoms of heart failure after an acute myocardial infarction (AMI) is associated with significantly longer survival and better quality of life. Further Leeds research showed the beneficial effects persisted long-term. The strategy of early initiation of ACEI is now a fundamental and routine part of the management of patients after AMI and has contributed to better survival and quality of life for patients around the world.
University of Bristol researchers at the Bristol Heart Institute (BHI) have pioneered the development and clinical take-up of the novel technique of off-pump coronary artery bypass (OPCAB) surgery. Over ten clinical trials and several large cohort analyses have assessed the impact of this technique on elective and high-risk patients. The results have shown that it is as safe as the conventional coronary artery bypass grafting (CABG) technique that uses a cardiopulmonary bypass pump and cardioplegic arrest. Most importantly, however, OPCAB significantly reduces the risk of post-operative complications, and reduces morbidity and mortality. It also uses less hospital resources, reducing time in intensive care and length of hospital stay. In 2011 (the last year for which data are available), 20% of CABG operations in the UK were carried out with the OPCAB technique and it has had significant take-up overseas (for example, 18% of CABG operations in the US and 21% in the EU in 2010). NICE has recommended the safety and efficacy of OPCAB surgery.
Patients with evidence of heart failure following acute myocardial infarction (AMI) have a particularly poor prognosis, with substantially increased risk of death and subsequent cardiovascular events. The Acute Infarct Ramipril Efficacy (AIRE) Randomised Controlled Trial (RCT) was an international trial designed and led by the University of Leeds. AIRE demonstrated, for the first time, that early treatment of patients with clinical evidence of heart failure following AMI with the angiotensin converting enzyme inhibitor (ACEI) ramipril significantly improved survival and quality of life compared with placebo treated patients. The strategy of early initiation of ACEI is now a cornerstone in the management of patients suffering from AMI, leading to a global improvement in post-AMI outcomes.
Approximately 26 million people live with heart failure worldwide. University of Glasgow researchers have been instrumental in proving the value, in landmark clinical trials, of bisoprolol, candesartan and eplerenone — three of the four classes of drug that reduce mortality, reduce hospitalisation rates and improve quality of life for patients with heart failure. These trials led directly to revision of clinical guidelines on heart failure management globally (including in Europe, USA, UK, Australia and Canada, all published since 2008). The Glasgow researchers have established heart failure as a healthcare priority and encouraged the introduction of specialist heart failure nurses, saving the NHS an estimated £8 million per year. Collectively, these advances have transformed the treatment and survival rates of heart failure patients worldwide.
Warfarin is an anti-coagulant drug prescribed to tens of millions of people in the UK and US who are at high risk of developing blood clots. Because individual sensitivity to warfarin varies in the population there is a risk of overdosing the drug and causing serious bleeding and even stroke in many people when starting treatment. In 1999 researchers at Newcastle University were the first to demonstrate a statistically significant link between a person's genotype and the appropriate dose of warfarin. In 2010 the US Food and Drug Administration (FDA) mandated inclusion of a table of dose recommendations based on genotype in the warfarin prescribing information leaflet accompanying the drug. Newcastle research forms the basis of the 2009 international standard algorithm for gene-guided dosing of warfarin. This approach has been adopted by large US medical centres and the FDA states that it will prevent 17,000 strokes a year in the US.
Sudden cardiac death causes 4.5 million deaths worldwide each year many of which could be prevented by implantable cardioverter defibrillators (ICDs), but these also carry risks. Research in the groups of Huang and Grace has led to diagnostic assays offering three times the predictive accuracy of current approaches in guiding cardiologists concerning indications for ICD implantation. The assay has been clinically trialled; since 2008, through the trial, the lives of three patients identified by the assay as at high risk were saved. Further work led by Grace and colleagues provided an improved, subcutaneous ICD (SICD); Grace also participated in a US-based clinical trial (NCT00399217) providing the evidence required for FDA approval supporting also later inclusion into NICE guidance. Since 2008 the SICD has been implanted in over 2500 patients in 16 countries.
This case study describes the healthcare impact arising from the trial and introduction of a new clinical treatment used in patients with acute coronary syndromes. Research at Sheffield provided robust evidence as to the effectiveness of the anti-thrombotic drug ticagrelor, which directly contributed to its approval by global regulatory authorities and its recommendation by the European Society of Cardiology and the National Institute for Health and Care Excellence as a first-line treatment in the management of acute coronary syndromes. South Yorkshire hospitals were early adopters in February 2012 and ticagrelor has been progressively adopted across other parts of the United Kingdom, with over half of UK hospitals now having adopted it. It has also been adopted in over 80 other countries.