Major research findings announced
A major study claims that routine use of heparin rather than bivalirudin could improve outcomes for heart attack patients, while at the same time reducing costs for healthcare organisations amounting to billions of dollars globally.
Listen to interview on BBC Radio 4 Today Programme with Dr Rod Stables (skip forward 40minutes to 06:40) -http://www.bbc.co.uk/programmes/b03z9k46
Researchers at Liverpool Heart and Chest Hospital NHS Foundation Trust (LHCH) have conducted what they believe to be the largest single-centre trial ever undertaken in cardiovascular medicine.
The study was also exceptional in that it recruited all patients presenting with a heart attack event, to create a population that reflects everyday clinical reality. Of the 1829 participants the oldest was 102 and the youngest 21; patients had home addresses on four continents.
The optimum treatment of a heart attack event is an emergency angioplasty and stent procedure, to re-open a blocked heart artery. This 22 month research trial compared the performance of two drugs, heparin and bivalirudin used as anticlotting agents in this setting.
The research findings were presented today (March 31st, 2014) at the American College of Cardiology 63rd Annual Scientific Session & Expo in Washington DC.
The results suggest that, when compared to bivalirudin:
- use of heparin was associated with a substantial reduction in the incidence of early recurrent heart attack
- use of heparin was also associated with marginally fewer deaths and strokes
- use of heparin would prevent three serious adverse events for every hundred patients treated.
Liverpool Heart and Chest Hospital is the largest single site specialist heart and chest hospital in the UK, providing tertiary services in cardiothoracic surgery, cardiology and respiratory medicine.
Dr Rod Stables, Consultant Cardiologist and Research Lead for Interventional Cardiology at LHCH, said: “These results are truly remarkable and could have important implications.”
“In the UK bivalirudin is approximately 400 times more expensive than heparin. Bivalirudin is in widespread use around the world.”
“Putting to one side the potential savings from better patient outcomes, we estimate that, by application of our findings, LHCH could make significant savings in drug costs alone. The potential for global cost saving is substantial.”
Unlike other medical trials, the study’s unique design involved the full range of patients experiencing the medical condition under evaluation and ensured that the results represent a ‘real world’ experience.
Dr Stables added: “For a variety of reasons, very sick patients, the elderly and frail, females, those from lower socio-economic groups and ethnic minorities, are often under-represented in clinical trials.”
“Therefore one of the distinguishing features of our trial was our fastidious dedication to include ‘every patient, every time’. This means that our results may better guide medical teams in making the right choices for the types of patients that they treat every day.”
Notes to editors:
(1) Can you please give a basic explanation of the study in lay terms?
Coronary artery disease (in which there is a gradual build-up of abnormal, often fatty, deposits on the inner linings of the heart arteries) remains the major cause of early death in the developed world. One of the most dramatic and dangerous manifestations of this problem is a ‘Heart Attack’. Doctors call this a myocardial infarction. Suddenly, and often without warning, an artery on the surface of the heart will block, cutting off the blood supply to a portion of the heart muscle. This condition, called ‘ST elevation myocardial infarction’ (STEMI), is best managed by emergency treatment to unblock the artery. This treatment is known as Primary Percutaneous Coronary Intervention or PPCI. Doctors use specialised equipment, inserted under local anaesthetic through a tiny incision in the wrist or at the top of the leg. Blood clot can be removed by suction and any narrowings stretched with a small balloon. In most cases, the lining of the artery is then supported by a metallic, tubular mesh scaffold called a ‘stent’ that is deployed into the artery.
Blood clot is the enemy in this setting. Special medication, to inhibit the body’s natural clot formation process is always given to make this PPCI treatment safer and more effective. In this study - HEAT PPCI, we have compared two anti-clotting (or anti-thrombotic) drugs - heparin and bivalirudin. Both drugs are in regular, worldwide use in PPCI but there is debate about whether one drug has any advantage over the other. In our study patients were randomly assigned to receive one of these routine medicines at the time of their emergency treatment for a heart attack.
Our study suggests that heparin may be a more effective agent, reducing the incidence of a range of so-called ‘Major Adverse Cardiovascular Events’ (death, stroke, recurrent additional heart attack events and repeat procedures). The most striking difference was observed in the rate of recurrent heart attack. Patients receiving bivalirudin were more likely to experience an early (or acute) blocking of their stent with new blood clot, mostly in the first 24 hours after their initial procedure. The rates of bleeding complications were similar in both groups of patients. Our results suggest that routine use of heparin, rather than bivalirudin could prevent 30 serious adverse events for every 1000 patients treated.
(2) Please share your full results and conclusions.
Results and conclusions are available on request.
(3) What do you consider the major finding (or the "take-home message") of your study for the average person reading about it?
Despite the fact that bivalirudin is approximately 400 times more expensive than heparin, our study suggests that patients receiving bivalirudin were more likely to suffer adverse events, mainly in the form of a recurrent heart attack event. There was no difference in the bleeding complications between the two groups. Our study also has some special and unique features in respect of its design and conduct. These are described in more detail below.
(4) How does this study compare to other, similar studies? Are your results consistent? What makes this study different?
Our study has a number of unique aspects. Almost all medical trials tend to recruit just a small proportion of all the patients who actually have the medical condition under consideration. Very sick patients, the elderly and the frail, patients from lower socio-economic group, females and those from ethnic minorities, are often not approached for study participation. This means that the results of some trials may not help guide treatment in the ‘real-world’ population. To overcome this problem, HEAT-PPCI sought to include ‘Every patient; Every time’.
In our trial, every patient for whom there was at least a suspicion of a heart attack was assessed for inclusion in the study. Remarkably, HEAT-PPCI randomised 100% of eligible patients. Every single patient who entered the emergency PPCI facility and was suitable for the trial was recruited in the study. This happened seven days a week, twenty-four hours a day for the better part of two years. This makes this study very different from probably all current research trials.
As this was a time critical, life-threatening emergency setting, we had full ethical approval for retrospective consent of patients. Patients are often in pain, frightened and have been given strong pain killing drugs with sedative effects. The study was discussed with surviving patients (or their appropriate representatives) at a time when they were able to give informed consent. Patients responded favourably to this concept and out of 1829 patients that we treated, just three refused and one withdrew consent. For those patients who sadly did not survive, the study obtained special permission to include their data so that the trial results do represent the complete picture.
Bivalirudin and heparin have been studied in the context of PPCI before so what else makes HEAT-PPCI different? In the past, bivalirudin alone has been compared against heparin given in combination with another agent to prevent blood clotting called a glycoprotein (GP) IIb/IIIa inhibitor. These studies have often shown higher rates of bleeding in the heparin arm - but we cannot exclude the possibility that this was because heparin-treated patients were given two anti-thrombotic agents rather than just the single agent given to those in the bivalirudin arm. HEAT-PPCI was more of a ‘classic experiment’ with one agent compared against another – heparin versus bivalirudin, head to head. GP IIb/IIIa inhibitors were used in specific circumstances in this study but their use was infrequent and comparable in both the heparin and the bivalirudin arm. In contrast to other studies, we found no significant differences in bleeding complications for heparin and bivalirudin.
(5) Did anything surprise you about your findings?
It is unusual and refreshing in healthcare to be able to report a trial which provides substantially improved clinical outcomes for patients, at markedly reduced costs. We embarked upon a unique trial design. Many aspects of the HEAT-PPCI study have never really been tried before. We were grateful and humbled that so many of our colleagues worked conscientiously and fastidiously in support of the trial to achieve these results.
Our key clinical finding, of reduced stent thrombosis and fewer heart attack events with heparin therapy has been observed in previous studies comparing the two agents, but in the other studies, this had to be balanced against increased bleeding. As we have explained above we have conducted the first direct comparison of the two agents when used in the classic design of a scientific experiment. Our study sought to evaluate the drugs by comparing outcomes in two groups of patients that were well-matched in all respects except for the mutually exclusive agents under test. In this setting, it seems that a clear advantage for heparin has emerged.
(6) What are the implications of your study for health care providers? For patients?
Routine use of heparin, rather than bivalirudin could improve outcomes for patients while at the same time reducing costs for healthcare providers. In our centre, performing about 1000 PPCI procedures a year, the cost saving would be about UK£500,000/year ($US 835,000). Translated to the global stage, the potential savings could amount to several billion dollars.
(7) Why is this an important study from your perspective?
We believe that HEAT-PPCI is a unique endeavour. We believe that it is the only major trial to have achieved 100% recruitment of all eligible patients. Our approach has allowed us to recruit a true, representative group of patients in a high volume UK centre. This was a considerable challenge! The oldest patient randomised was 102 years of age, the youngest just 21; patients had home addresses on four continents - some did not have English as a first language; several patients lacked the capacity for subsequent personal consent due to pre-existing conditions, (necessitating the involvement of third parties in the process); one patient sadly died in the minutes between randomisation and the start of their procedure.
To the best of our knowledge, this is the largest ever single-centre trial in cardiovascular medicine. Recruitment was completed in less than 22 months. This is testimony to the cohesion, dedication and discipline of the clinical teams at the Liverpool Heart and Chest Hospital who met all of the requirements of this trial, across 24 hours a day, seven days a week while providing complex interventional care in a high risk and emergency setting.
The study offers the prospect of improved clinical outcomes with substantial reductions in cost.
(8) Given the results of your study, what additional research in this area would you recommend?
There is an alternative form of heparin, called low molecular-weight heparin. There is some evidence that this may be another effective treatment agent and may be worthy of formal testing.
There is also doubt about the most effective strategy for the use of the adjunctive anti-clotting agents - the GP IIb/IIIa inhibitors.
(9) Please list any disclosures, including the source of funding for the study.
Unrestricted grants from The Medicines Company and Astrazeneca