Award Title: Personalised perioperative medicine to enhance recovery after major surgery.
Funder: Department of Health and Social Care

Abstract: Background: My proposal propels perioperative medicine into an era of precision medicine for the prevention and treatment of postoperative complications. Multimorbidity after surgery is an escalating, unmet healthcare need affecting millions of individuals worldwide each year. Transient organ injury/dysfunction after surgery impairs functional recovery, delays or prevents further cancer therapy and increases mortality. An early feature of perioperative organ dysfunction is myocardial injury, which reflects cell dysfunction across multiple organs, rather than cardiac ischaemia alone. My over-arching hypothesis is that perioperative multi-organ dysfunction is driven by marked reductions in cardiac vagal (parasympathetic) function, which is frequently impaired in around 35% of higher-risk surgical patients. Loss of cardiac vagal activity is an independent, predictor of morbidity/mortality, reflecting its' essential role for optimal exercise capacity. Surgical patients who sustain complications have profound parasympathetic dysfunction, as evidenced by multiple autonomic measures. This parasympathetic dysfunction is manifest by higher heart rate, which alone is strongly independently associated with perioperative myocardial injury and subsequent (non-cardiac) organ dysfunction. Organ protection through controlled lowering heart rate may therefore reduce multimorbidity after surgery. Plan: Patient-public representation and consultation will underpin the design, implementation and dissemination throughout two core projects. First, I will build on my previous clinical research by developing a low-cost, highly reproducible test that can be used to quantify cardiac vagal activity in the preoperative assessment clinic. This will introduce a personalised/stratified approach that will help us identify which patients may benefit most from lowering heart rate during the perioperative period. Second, in a randomised, double-blind, placebo-controlled trial, I will set out to test the hypothesis that patients undergoing noncardiac surgery with the highest perioperative risk should benefit from ivabradine by slowing heart rate to reduce myocardial injury and postoperative morbidity. I will randomise surgical patients on the basis of whether they have cardiac vagal impairment predictive of acquiring myocardial injury and other organ dysfunction, Given that the primary cardiovascular effect of ivabradine is to reduce heart rate, this trial will definitively answer whether elevated heart rate is a marker of risk or a modifiable determinant of perioperative outcomes. Re-positioning this readily available, cheap drug for perioperative use is rapidly deliverable and highly cost-effective if complications and need for hospital bed use can be reduced. At each stage, the clinical research will evolve with full public-patient involvement, which will enhance the design, implementation and reporting of this body of work. Impact: Given that the primary cardiovascular effect of ivabradine is to reduce heart rate, this trial will definitively answer whether elevated heart rate is a marker of risk, OR a modifiable determinant of perioperative outcomes. Additional elements of my fellowship proposal will equip me with a skillset that enhances both the delivery and implementation of precision medicine in healthcare services. Transitioning from translational basic/clinical studies by acquiring an in-depth understanding of clinical trial methodology, accompanied by further training in delivering precision medicine through robustly designed studies, will support my future leadership role in targeting the right treatments to the right patients at the right time.

Lay Abstract: Background: Increasingly complex surgical treatments are offered to more patients than ever before. In particular, older patients with serious medical problems are far more likely to undergo surgery today than even 20 years ago. Patients frequently develop medical complications in the days following surgery, including pneumonia and damage to the heart (which is usually undetected by doctors and nurses). Even temporary harm to other parts of the body after surgery prevents individuals from recovering to their normal levels of function. For many patients, this delays further necessary treatments, especially cancer therapies, and increases the risk of dying even after leaving hospital.The impact of these complications can last months and years, contributing to the increasing number of patients struggling to cope with multiple medical problems (called multi-morbidity). Multi-morbidity after surgery is an increasing and unmet healthcare need affecting millions of individuals worldwide each year. An early feature after surgery in many patients is damage to the heart, which reflects cell damage that is happening at the same time to many other parts of the body. Problems with a specialised nerve called the vagus nerve, that helps control the speed at which the heart beats, is often linked to heart damage and other complications after surgery. Poor vagus nerve activity causes higher heart rate, which is strongly linked to heart damage and coincides with other organs of the body not working normally. In this project, my aim is to protect both the heart and other body organs by lowering heart rate after surgery, to ensure that patients gain the best possible result from surgery with rapid recovery and as few complications as possible. Plan: I will develop a simple test using changes in patients' heart rate when they stand up to identify those at risk of complications after surgery because of poor vagus nerve function. I will use this test to select patients who may benefit from a drug which slows heart rate but does not affect other heart functions. The drug called Ivabradine, is already available on the NHS at minimal cost. This treatment may reduce heart damage and other complications after surgery. To make sure the trial is scientifically robust, patients will be randomly allocated to ivabradine or an identical placebo tablet to test which has most effects on heart damage and complications after surgery. Because the main effect of ivabradine is to reduce heart rate, this trial will clearly answer whether high heart rate is either a direct cause of harm to the heart or an effect of ongoing harm from another mechanism. Public & patient involvement: Patient representatives have advised and supported me throughout this proposal. They will lead focus groups and be included on the trial steering committee to represent the patient perspective in all aspects of design, implementation and reporting of this proposal. Expected outcomes:1. Demonstrate that a highly cost-effective drug can improve outcomes after major surgery in hundreds of thousands of patients most vulnerable to complications, for less than 5 per operation. This would reduce NHS expenditure through avoiding the prolonged need for hospital care and treatment of complications after surgery. 2. Establish whether high heart rate indicates more risk, or is a key clinical target to improve outcomes in many other acute clinical settings. 3. Introduce a vital step-change by demonstrating the need for, and benefit of, personalised perioperative medicine. 4. Through a structured training and personal development plan involving extensive patient-public consultation, this proposal will deliver a sustained pipeline of personalised perioperative medicine of the highest quality that can rapidly make surgery a safer treatment option for millions of patients worldwide.

Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: GENERIC HEALTH RELEVANCE