A multicentre randomised controlled trial of minimally invasive direct coronary bypass grafting versus percutaneous transluminal coronary angioplasty with stenting for proximal stenosis of the left anterior descending coronary artery.

AMIST investigated how best to treat patients who had a single blocked cardiac artery.  This is called the left anterior descending coronary artery (LAD), and it supplies the heart muscle with blood.  This study looked to compare:

  • minimally invasive direct coronary artery bypass grafting (MIDCAB), which is a type of cardiac surgery where the blocked artery is ‘bypassed’ with another piece of artery

with

  • percutaneous transluminal coronary angioplasty (PTCA), which is a cardiological procedure where a thin wire is inserted into the blocked artery and a small balloon is inflated to remove the blockage. To keep the vessel open a small mesh tube called a stent may be left in the artery.

The study looked at how well both procedures worked, as well as their value for money. The primary outcome measure that is used to compare how well the procedures worked, looked at how long before any symptoms returned or patients experienced other cardiac-related events such as a heart attack.

A total of 12,828 patients had an angiogram at participating centres from November 1999 to December 2001. An angiogram takes picture of the heart blood vessels to find out where they are blocked. 127 patients were consented to take part.

The study found no evidence that MIDCAB was more effective than PTCA. The procedure costs of MIDCAB were observed to be considerably higher than those of PTCA. Given these findings, it is unlikely that MIDCAB is value for money in treating patients with one blocked heart blood vessel.

 

Effectiveness and cost-effectiveness of serum B-type natriuretic peptide (BNP or NT-BNP) testing and monitoring in patients with heart failure (HF) in primary and secondary care

Heart failure happens when the heart becomes damaged, for example after a heart attack, and cannot adequately pump blood around the body.  B-type natriuretic peptide (BNP) is a chemical secreted by the heart in response to injury and its levels in the blood increases in people with heart failure.  Doctors have suggested that measuring BNP in the blood regularly and adjusting heart failure medications to lower BNP levels (BNP-guided treatment) may be better than adjusting medications based on symptoms alone.

Several studies have been conducted in which patients are allocated by chance to receive either BNP-guided treatment or standard treatment without having BNP measured. We combined the “raw” data collected on each participant in these studies in a meta-analysis, which is a statistical technique for combining the findings from independent studies.  We requested the raw data from all investigators who conducted these studies.

We also assembled a representative group of patients with heart failure in the UK and determined whether those who have BNP measured have better outcomes than those who do not. For this we used data that are routinely collected by hospitals and GP practices in the UK.  The results from Monitor will help doctors to decide whether BP-guided treatment should be offered to all patients with heart failure in the UK. 

Publication

The paper for the study can be read here: https://systematicreviewsjournal.biomedcentral.com/articles/10.1186/2046-4053-3-41

 

Early and midterm outcome after off-pump and on-pump surgery in Beating Heart Against Cardioplegic Arrest Studies (BHACAS 1 and 2): a pooled analysis of two randomised controlled trials

Cardiac surgery was traditionally performed ’on-pump’, which means that during the operation the heart is stopped and blood is pumped round the body by the heart lung machine (the ‘pump’).  At the time of the BHACAS studies, coronary-artery bypass surgery on the beating heart was being used in more and more patients (‘off-pump’).  In this operation, the heart continues to beat.  However, there were no randomised controlled trial to compare the midterm effects of each type of surgery. We did two randomised trials to compare the short-term morbidity associated with off-pump and on-pump myocardial revascularisation. Our aim was to pool the results to assess midterm outcomes.

From March 1997, to November 1999, we randomly allocated 200 patients to off-pump and 201 to on-pump coronary surgery. In Beating Heart Against Cardioplegic Arrest Study (BHACAS) 1, we excluded patients who had had myocardial infarction in the past month or whose operations were more challenging on the beating heart. In BHACAS 2, we included such patients. Primary outcomes were all-cause mortality and cardiac-related events at midterm follow-up (1-3 years).

Off-pump coronary surgery significantly lowers in-hospital morbidity without compromising outcome in the first 1-3 years after surgery compared with conventional on-pump coronary surgery.

Two to four years after surgery, patients randomised to off- and on-pump had similar symptoms, generic and disease-specific QoL.

Despite this evidence some surgeons were unwilling to adopt off-pump surgery as they were worried about the long-term quality of the bypass grafts performed on the beating heart.

We conducted a follow-up study to BHACAS 1 and 2 to compare long term outcomes in these patients.

Participants were followed up at 6 to 8 years after their operation to assess graft patency (i.e. If the bypass graft had become blocked), major adverse cardiac-related events such as heart attack, and health-related quality of life. The bypass grafts were assessed by using multidetector computed tomographic coronary angiographic analysis with a 16-slice scanner (CT scans). Two blinded observers classified proximal, body, and distal segments of each graft as occluded or not. Major adverse cardiac-related events and health-related quality of life were obtained from questionnaires given to participants and family practitioners.

Long-term health outcomes with off-pump coronary artery bypass are similar to those with coronary artery bypass grafting with cardiopulmonary bypass when both operations are performed by experienced surgeons.

 

Improving Outcomes from Out of Hospital Cardiac Arrest: The Cardiac Arrest Individual Registry and Outcomes (CAIRO) Programme

A cardiac arrest occurs when the heart stops beating suddenly. It is one of the most extreme medical emergencies. 60,000 people suffer an out of hospital cardiac arrest (OHCA) in the United Kingdom (UK) each year, with resuscitation attempted in less than half, and less than 10% surviving to hospital discharge. Recently available figures also show that there is considerable variation throughout England in both the frequency with which a heartbeat is regained (return of spontaneous circulation; ROSC), and survival. With support from healthcare commissioners, the hospital care of OHCA is becoming centralised in fewer ‘heart attack centres’. Alongside this concentration of services, we plan to implement a programme of research designed to monitor and improve patient care from the initial ambulance response right through to, and beyond, hospital discharge. This is called the ‘Cardiac Arrest Individual Registry and Outcomes (CAIRO) Programme’.

At the centre of this research was a detailed patient registry: the CAIRO database. This will allowed us to link data from different sources to track each cardiac arrest patient from their initial collapse through to hospital discharge and, with the patient’s consent, follow-up assessments of further progress at subsequent time points. We aimed to establish the CAIRO database in our own ‘heart attack centre’ (University Hospitals Bristol National Health Service (NHS) Foundation Trust; UH Bristol), and then in two neighbouring hospitals (North Bristol NHS Trust and the Royal United Hospital Bath NHS Trust), with the hope tp proceed wider implementation across the Southwest region and nationally. We aimed to demonstrate that it is feasible to access and link information about patients, by obtaining the data required to address a number of important research questions about patient outcome covering the patient pathway.

The full paper can be read here: http://emj.bmj.com/content/32/6/e17.1

 

Coagulation and platelet laboratory testing in cardiac surgery

Blood transfusion is a lifesaving treatment for excessive bleeding that is used commonly in patients having major surgery. However, blood transfusion is also expensive and has harmful effects on the
immune system and circulation of recipients. As a consequence, the need to improve how blood is used was recognised as an NHS strategic priority in 2007. Heart surgery often causes excessive bleeding and accounts for over 6% of all blood transfused in the UK. One important reason for this statistic is that heart surgery patients often have abnormal blood clotting. This can be because of tablet medication for heart disease taken before surgery or as an effect of the techniques used to perform heart surgery.

We investigated whether it is useful to perform blood tests either just before, or just at the end of heart surgery to identify exactly how the blood clotting system is abnormal in each patient. The results of these tests could potentially lead to recommendations to give specific treatments to patients to improve blood clotting and reduce bleeding and blood transfusion. We performed this research over 24 months by taking two blood tests from 2400 consecutive patients having heart surgery at the University Hospitals Bristol. The blood was analysed using specialist blood clotting tests so that we could identify exactly what abnormalities were present. We tested the blood using blood clotting analysers that are designed to be used in the operating theatre to find out how often these analysers correctly identify a clotting abnormalities and what additional test information is required to give the correct diagnosis when they do not. We also investigated how our laboratory test results relate to the amount of bleeding and other complications in our patients. This information showed the benefits of performing different kinds of tests so that we could recommend the best tests to perform in future.

 

 

 

Coronary artery grafting in High RISk patients randomised to Off Pump or On Pump Surgery

Despite advances in medical therapy and percutaneous coronary interventions (PCI) there is good evidence that CABG offers superior survival and freedom from repeat intervention in patients with multivessel CAD. For example, in the recently published New York State registry of almost 60,000 patients, after risk stratification for cardiac and non-cardiac comorbidity, there was a significant reduction in mortality (absolute difference of 5%) and a seven fold reduction in the need for repeat interventions at three years in patients undergoing CABG rather than PCI using stents. Predictions that drug eluting stents will significantly reduce the need for CABG are premature because, although these stents reduce the incidence of restenosis compared to bare metal stents, three large meta-analyses have shown that they do not improve survival or reduce the incidence of subsequent myocardial infarction.

There are two reasons why CABG is likely to remain a superior treatment to PCI over the longer term: (i) CABG protects whole zones of proximal myocardium (as the graft is placed to the mid coronary vessel beyond all proximal disease); (ii) PCI frequently results in incomplete revascularization which adversely affects survival proportional to the incompleteness of revascularization. Currently around half a million patients worldwide undergo CABG each year. There is a real possibility that these numbers will increase with a growing elderly population and an increasing epidemic of diabetes and obesity which all predispose to the development of CAD and an increasing realisation that PCI may merely delay definitive treatment.

Publication 

The paper for this study is available to read here: https://www.journalslibrary.nihr.ac.uk/hta/hta18440/#/abstract

 

The Effectiveness of Community versus Hospital Eye Service follow-up for patients with neovascular age-related macular degeneration with quiescent disease: a virtual trial

Wet, or neovascular, age-related macular degeneration (nAMD) is a condition which causes severe sight loss and is the most common cause of blindness in older people in the UK.  nAMD develops when abnormal blood vessels form in the part of the eye responsible for central vision (the field of vision when looking straight ahead).  The current treatment for patients with nAMD is monthly observation and administration of a drug which is designed to block one of the chemicals responsible for the growth of new blood vessels.  The drug is injected into the eye when the disease is active and stopped when the disease process is controlled.

Hospital eye doctors (ophthalmologists) continue to see patients monthly, even when no injections are needed, because there is a very high risk of needing to restart treatment at some point in the future.  This is burdensome for patients and for busy hospital clinics, particularly since the need for monthly treatment diminishes over time. 

Publication

The Echoes study aimed to determine whether follow up by optometrists in optician practices in the community is as good as follow-up by opthalmologists.  Rather than carrying out a new trial, eye images (colour fundus and ocular coherence tomography images) collected during a large UK based multicentre clinical trial (the IVAN trial) were used to determine whether optometrists can detect disease activity and make the same decisions about re-treatment as opthalmologists. 

The NIHR have created a summary which can be read here: http://www.nets.nihr.ac.uk/news/all/2016/routine-monitoring-of-eye-condition-effective-in-the-community and the full paper accessed via this link: http://bmjopen.bmj.com/content/6/7/e010685.full

 

A randomised controlled trial of alternative treatments toInhibit VEGF in Age-related choroidal Neovascularisation (IVAN)

Wet or neovascular age-related macular degeneration (nAMD) is a condition which causes severe sight loss in older people. This condition is due to a pathological process in which new blood vessels grow into the central region of the retina of the eye, known as choroidal neovascularisation (CNV). These vessels are leaky and lead to the accumulation of fluid between and within the layers of the retina with serious adverse effects on central vision.

Lucentis® is an 'anti-VEGF' drug which is injected monthly into the eye which causes these blood vessels to stop leaking and to shrink. With treatment, eyesight improves in a quarter of affected people and, in the majority (90% or more), eyesight does not deteriorate over two years. These results represent a major improvement over previous treatments. Another anti-VEGF drug, Avastin® (from which Lucentis was derived), may be equally good and is considerably less expensive but its efficacy and safety have only been studied in case series.

The IVAN trial wass a head-to-head comparison of the efficacy and safety of Avastin® and Lucentis®. The IVAN trial studied whether the number of treatments needed can be reduced by comparing monthly anti-VEGF treatment for 2 years with monthly anti-VEGF treatment for 3 months only, with careful monthly review and re-starting treatment if any signs of disease recur.

The study randomised patients to various combinations of active treatment; all patients recruited to the trial received anti-VEGF treatment in one or other combination. Eyesight was assessed at each visit and information collected on quality of life and the costs and burden of illness, which was compared between the different groups after 1 and 2 years follow-up.

Two Year Findings

Tthe two-year findings of the IVAN trial, led by Professor Usha Chakravarthy (Queens University) and co-ordinated by Bristol CTEU, were presented in a planetary session at the Association for Research in Vision and Ophthalmology (ARVO) conference in May 2013. The results show that the two drug treatments Lucentis and Avastin are equally effective in treating neovascular or wet age-related macular degeneration (wet AMD).

Publications

Bristol University Press release 

The Lancet- IVAN two year findings 

 



 

PATIENT-SPECIFIC CEREBRAL OXYGENATION MONITORING AS PART OF AN ALGORITHM TO REDUCE TRANSFUSION DURING HEART VALVE SURGERY: A RANDOMISED CONTROLLED TRIAL

PASPORT

During heart surgery, doctors take measurements to make sure that a patient has enough oxygen for their body to function properly. For example, they check the oxygen supply to the whole body by measuring the amount of oxygen in the blood. When these ‘whole bod’ measures of oxygen show that the body is not getting enough oxygen, doctors try to improve the oxygen supply.

During surgery, doctors also monitor the amount of red cells in the patient’s blood (known as the ‘haematocrit’). Red cells are important because they carry oxygen around the body. Doctors try to keep the haematocrit above a set level because it is assumed that, otherwise, the body will not receive enough oxygen. If a patient’s haematocrit falls below the pre-set level, doctors may give the patient a blood transfusion to try to increase the amount of oxygen available to the body.

These practices are not ideal. Sometimes the haematocrit and the oxygen supply to the body can be normal even when oxygen levels in specific organs and tissues are low. Also we know that transfusing blood to keep the haematocrit above a pre-set level does not always increase the oxygen levels in specific body organs unless they are very low to begin with and although blood transfusions may be beneficial, they can cause harm. Doctors therefore want to avoid unnecessary transfusions where possible.

We think that monitoring oxygen levels in specific organs during surgery would be a better way to decide whether a blood transfusion is needed. Developments in technology mean that we can safely measure the oxygen level in the brain during surgery using sensors placed on the forehead. Using this method, we can adjust the oxygen supply and blood transfusion during surgery to the needs of the individual patient, instead of applying the pre-set level to all patients (as we do now). We believe that the brain is the best organ to monitor because it is most sensitive to decreases in oxygen.

The Pasport study investigated whether monitoring the oxygen level in the brain improves the health of patients after the operation and reduces the number of blood transfusions. We compared this new method with the current method of monitoring the haematocrit and oxygen supply to the whole body to decide when to transfuse blood.

The Pasport protocol paper was published in December 2015.

 

A study of platelet inhibition, using a ‘point of care’ platelet function test, following primary percutaneous coronary intervention for ST elevation myocardial infarction (PINPOINT-PPCI)

Heart attacks are increasingly being treated with immediate re-opening and placement of a metal-mesh tube (stent) in the blocked heart artery. In addition to scaffolding the artery with a stent, drugs are used to thin the patient’s blood. We have recently changed the drugs given to patients presenting to the Bristol Heart Institute with heart attacks. The drugs we have selected are potent blood thinners and have been shown to act very fast.

In this study we measured the level of blood thinning achieved at the end of the stenting procedure. We thought that there may be a variable response to the blood thinning drugs and patients with a low response may be at increased risk of blood clotting problems. We described the relationship between the measure of blood thinning at the end of the procedure with the time given for the drug to take effect and ultimately with complications developed within the first 30 days following the stenting procedure.

Publication 

The results of this study can be read here: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0144984 

 

Propofol cardioplegia for Myocardial Protection Trial: Prompt

During cardiac surgery the heart is isolated from the rest of the circulation (bypassed) and a heart-lung machine is used to oxygenate the blood and pump it around the body. The heart is stopped, and provided with nutrients, by a (cardioplegic) solution that is injected directly into the heart arteries from time-to-time. This allows the surgeon to operate on the heart while it is still and not filled with blood but looking after the heart in this way during the operation is not ideal. The heart muscle can become short of oxygen and, when the heart is restarted and blood starts to flow through the coronary arteries again, the muscle can be harmed. The damage is believed to be caused mainly by the formation of highly reactive molecules known as ‘free radicals’ in the heart muscle during the time it is short of oxygen.

Propofol is a general anaesthetic widely used in cardiac surgery and recent research suggests that propofol could protect the heart muscle against damage from free radicals. We wanted to investigate the benefit of adding propofol to the cardioplegic solution in patients having isolated coronary artery bypass grafting (CABG) or aortic valve replacement surgery (AVR) using the heart-lung machine.
We assessed the benefits of adding propofol by studying chemicals released by the heart and other organs in the body when they are damaged or stressed. We measured these chemicals in blood samples taken before, and after the operation, and in very small pieces of heart muscle obtained during the operation. Removing small pieces of heart muscle during surgery is a well established research procedure that has no effect on the heart.

Publication 

The results paper for the PROMPT study is available here: http://www.sciencedirect.com/science/article/pii/S0022522315010685

 

A randomised controlled trial of median sternotomy vs. anterolateral left thoracotomy on morbidity and healthcare resource use in patients having off-pump coronary artery bypass surgery (SteT)

Previous randomised controlled trials have compared the effectiveness of coronary artery bypass surgery on the beating heart without the heart-lung machine (off-pump coronary artery bypass, OPCAB) with conventional bypass surgery, by arresting the heart and using the heart-lung machine to pump blood around the body.  These trials have concluded that OPCAB reduces post-operative morbidity and hospital costs without compromising mid-term clinical outcome.  Because patients who have OPCAB are less likely to experience complications or transfusion, they recover quicker and leave hospital sooner – a “win-win” situation for both patients and the NHS.  It has been suggested that recovery may be even faster if the operation is carried out through an incision in the left hand side of the chest (thoracotomy) instead of through a central, vertical incision through the sternum (sternotomy).  In a recent study of 200 patients who had a thoracotomy incision, less than 20% of patients required ventilation in intensive care, and most patients were discharged within 4 days, shorter than is usual with OPCAB through a sternotomy; for example, since the year 2000 in our institution, the majority of patients having OPCAB through a sternotomy were ventilated for several hours and less than 5% were discharged within 4 days.  However, this simple comparison of the outcome of thoracotomy and sternotomy incisions is likely to be biased since patients may have been selected for the thoracotomy study, and the two kinds of incision were used in operations carried out by different surgeons in different institutions.  Therefore, we carried out an unbiased, “head-to-head” comparison of thoracotomy and sternotomy incisions for off-pump coronary artery bypass, controlling for all factors other than the specific surgical methods.

Results 

The results of this study can be found here: https://www.ncbi.nlm.nih.gov/labs/articles/22944093/

 

A multi-centre randomised controlled trial of Transfusion Indication Threshold Reduction on transfusion rates, morbidity and healthcare resource use following cardiac surgery (Titre 2)

Indications for blood transfusion after cardiac surgery are poorly defined. Unnecessary blood transfusions increase healthcare costs both directly, because blood is an increasingly scarce and expensive resource, and indirectly, due to complications associated with transfusion. Transfusion may cause complications by reducing patients' ability to fight off infection and respond to the stress that surgery puts on the body, as well as (rarely) by transmitting viral infections present in donor blood. In the UK, cardiac surgery uses more than 6% of all donor blood (and about 10% of donor blood in the UHBristol, a tertiary cardiac surgery centre). Although the benefits of red cells for managing life-threatening bleeding are clear, the majority of decisions to transfuse after surgery are made on the basis of a patient's haemoglobin (Hb) level (a measure of the ability of the blood to transport oxygen around the body). The level that causes a doctor to transfuse a patient varies widely and randomised trials in non-cardiac surgical fields have shown that lowering the level that 'triggers' transfusion reduces complications as well as the use of blood.

The research was carried out in a number of UK hospitals. Patients whose Hb level dropped below the level at which transfusion is conventionally given were assigned by chance to have decisions made: (a) more or less as they are now, or (b) only when the Hb level drops to a lower, 'restrictive' level. The primary outcome was the number of infectious (sepsis) and ischaemic (stroke, heart attack or kidney failure) complications that occurred during the first 3 months after surgery. 

Publication

Liberal or Restrictive Transfusion after Cardiac Surgery - full paper can be accessed here

Webinar

Dr Rachel Brierley recently hosted a webinar entitled 'Methods to manage the randomisation and treatment of patients 24/7 in a large multi-centre RCT' as part of the HTMR Trial Conduct Working Group Webinars 2016-2017. If you would like to watch a recording of the webinar, it is available here: https://www.mrc-phru.ox.ac.uk/webinars/