Surviving a heart attack

How ticagrelor saves lives

Ticagrelor has saved the lives of thousands of heart attack patients around the world. Its journey from discovery over twenty years ago to world-wide treatment was the product of one of the largest clinical trials in the world, involving 18,000 patients in over 40 countries.

SURVIVING A HEART ATTACK | HOW TICAGRELOR SAVES LIVES

Introduction

Today, your chance of dying as a result of one of the UK’s most common but terrifying health ordeals has been substantially reduced as a result. And it started with one academic conducting experiments in a test tube...

Over thirty years ago, on a cloudy, warm Saturday in September, my extended family – the whole motley crew of aunts, uncles, teenagers, babies, second cousins and great aunts – gathered in my Aunt Judith’s back garden awaiting the arrival of my granny and grandfather for their 40th wedding anniversary. But they never arrived. My grandfather had suffered a serious heart attack just as they were leaving. He made it to hospital and survived. But a few years later he would go on to have a repeat episode that killed him.

Most of us know at least one person who has had a heart attack. Heart disease is still one of the biggest killers in the UK and someone is admitted to hospital every three minutes for a heart attack. 70,000 people die from the condition every year.

Whilst your chances of surviving your first heart attack remain high if you make it to hospital in time – around 95% – there is still a significant risk of recurrent episodes. Around 20% of patients have another heart attack or stroke in the first three years following their first, which can result in death.

Over the last century, medical research has defeated and disarmed terrifying killers such as cholera or polio. But heart attacks give us nightmares. And that’s in part because they come in disguise. It’s not always obvious what the signs are. It could feel like the typical crushing chest pain that comes to mind when we think of heart attacks, but it could be more like indigestion. You could just feel unwell with sweating or breathlessness. In short, if you’re having one, you won’t necessarily know it…

Professor Rob Storey

Professor Rob Storey is Professor of Cardiology at the University of Sheffield, where he has headed a thrombosis research group since 2002. In addition, he is Academic Director and an honorary Consultant Cardiologist for the Cardiology and Cardiothoracic Surgery Directorate, Sheffield Teaching Hospitals NHS Foundation Trust.

CHAPTER ONE

What a heart attack feels like

“Careful – you’ve just sat in the death seat,” my photographer’s warned as he settles into our host’s armchair.

A dynamic and strong-willed 81-year-old with a twinkle in his eye, Ken Bury doesn’t seem like someone who had a heart attack a matter of weeks ago. As he leads us through his spotless house pointing out the kitchen he built, the garden fence he put up himself last month, the fish in the dining room and his electric blue budgie Mickey, it feels safe. Not the kind of place someone would almost die in.

Ken wasn’t exerting himself at the time he had his attack. He was relaxing in his favourite chair watching Saturday night TV when he was first niggled with what he describes as: “a feeling I’d never had before… but never what you’d call pain”.

He shrugged it off and went to bed. But around one 1am he awoke feeling unwell – and something was telling him it was his heart.

From here Ken’s description of events becomes hazier (it’s common to suffer memory loss post-episode due to losing blood flow to the brain). He remembers going downstairs, sitting in the armchair in his lounge and googling the symptoms of a heart attack. According to the call history on his mobile it was around this time that he rung 999. When the ambulance arrived, he’d lost consciousness and was in the full throes of major cardiac arrest. His heart had stopped beating and he wasn’t breathing.

The paramedics quickly got to work, re-starting his heart with a defibrillator shot. “It was about as near to dying as you can get,” Ken explains. If the paramedics had arrived even a few minutes later, he wouldn’t have survived. And in this specific sense he was lucky. Only around 7–8% of people in whom resuscitation is attempted survive a cardiac arrest, and there is approximately a 10% reduction in survival for every minute’s delay in providing defibrillation.

Ken was experiencing what’s known as a ‘widowmaker’ heart attack. His left-anterior descending artery was completely blocked by a blood clot, starving his heart of oxygen. As his heart muscle was dying, it was desperately trying to compensate by beating 300 times a minute. He was rushed to the Northern General Hospital for emergency Percutaneous Coronary Intervention (PCI) to remove the clot.

PCI – or angioplasty – is a fiendishly delicate procedure, but it’s bread and butter to a cardiologist. It  involves running a tube up through the artery in the wrist or groin to unblock the small blood vessel supplying the heart muscle. Within 20 minutes Ken’s clot had been removed and he was taken to the ward to recover. He woke up five days later, “The nurse told my granddaughter it was a ‘whopper’. She’d been in the cardiac unit for three years and this was the biggest she’d seen.”

Had Ken been born 40 or even 20 years earlier, it’s likely that he wouldn’t have made it. In the 1960s and 70s, heart attacks were killers – fatal in over 70% of victims. Saving Ken’s life from that first startling attack is down to a number of factors – not least the incredible progress made in cardiology over the last 40 years. Saving him from a second is where ticagrelor comes in. 

“The nurse told my granddaughter it was a ‘whopper’. She’d been in the cardiac unit for three years and this was the biggest she’d seen.”

Ken Bury
CHAPTER TWO

Volume control for blood clots

Professor Rob Storey is an academic clinician, a practising cardiologist who performs procedures including PCI, the procedure that saved Ken’s life – and a researcher at the University of Sheffield who helped develop ticagrelor.

It’s a combination that clearly motivates him: “It can be distressing when things go wrong for your patients and this is a major driver to improve or discover new treatments.” Or as one of Storey’s clinical research fellows, Dr Wael Sumaya describes it, “When you’re a clinician and you’re seeing one patient, you’re only helping one patient. When you’re doing research you have the potential to help millions of patients. It also helps your teaching – when you’re teaching students about your research you understand it better, which means you teach it better. That’s the beauty of combining academic and clinical work.”

In the 1990s, when Rob was fresh out of medical school and training to become a cardiologist, death rates from heart attacks were still very high, despite the development of technologies such as stents and pacemakers. Blood clots had only recently been discovered as the cause and aspirin became the standard treatment for preventing further clots. However, the relatively weak effects of aspirin had prompted a flurry of research into new anti-clotting drugs. One of the drugs clopidogrel would soon become the main drug prescribed to patients following a heart attack. However, there were drawbacks with clopidogrel, whether or not it worked was a complete lottery, based on a patient’s genetics and body characteristics. Storey was keenly aware of the drug’s shortcomings and the need for something better.

Enter pharmaceutical company Astra (later AstraZeneca), who had been working on a new intravenous anti-clotting therapy known as cangrelor, it was the precursor for ticagrelor. Recognising the potential of these drugs, Storey approached Astra to carry out research on cangrelor, he explains: “It was very exciting because the processes I was researching hadn’t been well-documented… it was completely unexplored territory.”

Cangrelor and ticagrelor function as platelet aggregation inhibitors, targeting and inhibiting the activation of the P2Y12 receptor on the surface of platelet cells, reducing their ability to clot. The receptor plays a profound amplification role in platelet activity. Rob describes its effect as being like a volume control. Activate the receptor and you turn the volume up. Block it and you turn the volume down.

“The advantage is that with cangrelor and ticagrelor you don’t switch the sound off altogether.” Rob outlines. “The platelets still have some activity – to stop bleeding you still need platelet activity. So it’s a very neat way of preventing clots forming in the arteries.”

Storey was initially the only researcher outside of Astra with access to cangrelor. Proving its effectiveness in the lab and demonstrating this to doctors and scientists around the world was his responsibility. And it was already showing a more consistent and reliable response in different blood samples – potentially a major step forward from the current treatment.

He was also the first doctor to ever administer it to a patient in the late 90s. “Although it was 20 years ago, I remember this brave gentleman who volunteered to take part in the trial after being admitted to hospital with a heart attack the evening before.” says Storey. “Starting the drug was an exciting moment as I felt there was a strong chance it was going to benefit him. We also gained a huge amount of information through blood sampling and testing how long he bled for whilst we gave different doses of cangrelor. I think patients who signed up for these studies had a sense of this pioneering work that was potentially going to help them. It’s so important to remember the dedication and courage of any patient who volunteers for clinical research, it allow us to improve treatments that will in the end benefit all patients.”  

Rob went on to advise Astra on the process of turning cangrelor, a treatment administered through an intravenous drip, into ticagrelor – an oral treatment that could be prescribed for 12 months or more. Then came the immense challenge of helping in the design of a clinical trial to prove to the medical world the drug’s effectiveness.

It’s so important to remember the dedication and courage of any patient who volunteers for clinical research, it allow us to improve treatments that will in the end benefit all patients.”

Professor Rob Storey
CHAPTER THREE

Double blind, double dummy

PLATO (Platelet Inhibition and Patient Outcomes) was a clinical trial on a massive scale. It brought together cardiologists and scientists from around the world to collect data from over 18,000 heart attack patients in 43 different countries.

Storey was advisor on the executive committee and also provided 90 Sheffield patients for PLATO. It was a hugely complex operation with patients randomised to ticagrelor or clopidogrel in a double blind, double dummy test, taking either active ticagrelor or dummy ticagrelor or active clopidogrel or a dummy.

Ticagrelor would need to show significant gains if it were to supersede clopidogrel. The trial took almost two years to complete. The results were published in the New England Journal of Medicine and, prior to this, unveiled to members of the executive committee at a meeting near Uppsala in Sweden. Rob’s flight was delayed so by the time he had his hand on the report, the discussion in the room had moved on. But the statistics on the page still reverberated. Ticagrelor reduced mortality rates in patients from 5% to 4% – preventing 1 in 5 deaths. It would save the lives of hundreds of thousands of patients all over the world.

“What goes through your mind when you see that kind of impact from your research? You’re saying ‘Yes!’’’ Rob exclaims. “Having already carried out extensive research on ticagrelor and seen its impact on patients, I was confident that it would show an advantage over clopidogrel as a more potent and reliable platelet inhibitor. However, I had no idea the extent to which the data would show this benefit in mortality rates.”

PLATO produced the ground-breaking results Professor Storey and his colleagues were hoping for. It opened the way for ticagrelor to be approved in 2011 by the National Institute for Health and Care Excellence (NICE) as a cost-effective treatment for heart attack patients. South Yorkshire was one of the first areas in the world to adopt the drug, and it has become the main anti-clotting treatment across the UK and the world.

Drug discoveries save lives. But the effect of the research behind ticagrelor has had even larger outcomes. Ten years later, papers are still being produced from PLATO – 74 so far, with over 100 expected altogether, all helping to advance medical research. Ken Bury was so impressed with his treatment that he’s volunteered for a trial of another new drug tackling the causes of heart attacks. Dr Wael Sumaya, Professor Storey’s clinical fellow, uses research-led teaching on drug discoveries to inspire the next generation. Students come to understand the life-changing consequences of developing drugs like ticagrelor, with junior doctors actually seeing the results on their patients.

CHAPTER FOUR

What happens next?

So what happens next after a success story like ticagrelor? Rob doesn’t stop there: “My instinct as a researcher has always been to keep raising new hypotheses – you generate new questions and you get answers, but then that creates new questions.”

He is currently working on a new potentially life-saving project with a team of researchers that includes Dr Wael Sumaya. Originally from Damascus, Syria, Wael came to the University of Sheffield eight years ago to train as a cardiologist. Like Storey he also wanted to be a researcher and gained a fellowship from the British Heart Foundation to support Storey’s new project. Wael hopes this new research area will be an additional piece of the puzzle in reducing mortality rates amongst the 20% of patients who still don’t respond to post-heart attack treatment.

He’s working from blood samples collected during PLATO to analyse the ‘protein arm’ of clotting – the process which produces fibrous substance needed to form blood clots. The research has revealed that for a number of patients it proves much harder to break clots down and disperse them. And this can predict whether or not a patient will respond to anti-clotting treatment and survive in the aftermath of a heart attack.

This new development, which was presented to the American Heart Association and published in the European Heart Journal, could hold the key to unlocking a new drug, which will help those still at risk of dying from a second heart attack.  

Perhaps one day, thanks to medical research, ‘heart attack’ will no longer strike the same fear into us. As Rob contemplates: “We can definitely still make progress. There’s always more that we can do. If we could eventually say that once people get to hospital there’s virtually no risk of dying from a heart attack that would be incredible. That’s what I’d like to see.”

Written by: Lizzie Ellen, Communications Officer, The University of Sheffield

There’s always more that we can do. If we could eventually say that once people get to hospital there’s virtually no risk of dying from a heart attack that would be incredible. That’s what I’d like to see."

Professor Rob Storey