The X Factor

^{There’s a revolution coming. A sea change in clinical care is just over the horizon and it promises a life-saving opportunity for millions of people worldwide, so says one of the most internationally respected experts on anticoagulant therapy, Professor Alexander Turpie.}

And he should know. The Professor of Medicine at McMaster University in Ontario, Canada, has been at the forefront of evaluating anti-thrombotic agents for more than forty years, from his 1965 study in East Africa on the anticoagulation action of Puff Adder venom to Principal Investigator in the groundbreaking RECORD programme - the largest clinical investigation ever conducted of an oral anticoagulant in the prevention of venous thromboembolism (VTE) after knee or hip replacement surgeries.

On a whistle-stop visit to Ireland Prof Turpie spoke to Scope of his excitement in the wake of huge strides now being made in anticoagulant therapy for the first time in decades. “We really are on the verge of something new in anticoagulants, and all the data that we’re seeing is extremely promising. I suspect that by two or three years from now we will have a complete change in anticoagulant management,” he predicts.

And not before time, when you consider that for 65 years, in terms of oral anticoagulants, all we've had are the vitamin K antagonists, the most commonly used being Warfarin. Although these drugs are effective, they have numerous limitations. They have a slow onset of action, which requires them to be over-lapped with parenteral agents for an immediate anticoagulant response when treating someone with established thrombosis.

Another difficulty is the variable dose requirement, and this variability reflects genetic polymorphisms in Warfarin metabolism that are quite common. It also reflects the effects of food and multiple drugs on the dosage requirements. This varying anticoagulant response to the vitamin K antagonists requires monitoring, which is inconvenient for patients, inconvenient for doctors, and often leads to an under use of these drugs in situations where patients should be on them.

But Prof Turpie is optimistic for the future: “There has been enormous developments in anti-thrombotic therapy over the past twenty years and it’s largely because we have been able to demonstrate that anticoagulant drugs work in many situations, Heparin and Warfarin, but there has been a whole new series of anti-coagulant drugs which have the potential to change how we practice.

“There are many areas where anti-coagulant drugs or blood thinners have been effective, one is the prevention of deep vein thrombosis and pulmonary embolism - in patients who have orthopaedic procedures for example - they are effective in the treatment of thrombosis, they are effective in preventing stroke in patients who have atrial fibrillation and they are also effective in the management of some patients who have acute coronary syndrome, so it’s a very broad spectrum of clinical uses.

“Many are given by injection and the only ones that are given by mouth currently are the vitamin K antagonists, one of which is Warfarin, but when one looks at the clinical needs of anti-coagulant therapy we really need a new drug that is given by mouth that doesn’t have the limitations of Warfarin, which are the requirement to monitor, interactions with drugs and food etc, and not least the varying response among individuals.”

The development of new drugs in this area is based on a greater understanding of coagulation. Most of the promising new agents are targeting single coagulation factors where as, in the past, the drugs have targeted multiple coagulation factors.

Parenteral agents, such as heparin and low-molecular-weight heparin, target multiple enzymes in the clotting cascade, predominantly thrombin and Factor Xa, but also clotting enzymes higher up in the coagulation cascade, and it is not possible to control how they target one over the other.

Vitamin K antagonists are even more problematic because they lower the functional levels of the vitamin K-dependent clotting factors - prothrombin, Factor VII, Factor IX, and Factor X - but the rates at which they do that are variable.

“It really makes sense to focus in on one or the other of the key clotting enzymes in coagulation,” explains Prof Turpie. “Most of the attention right now is focused on either thrombin (Factor IIa) or Factor Xa and there is some exciting results with some of these new oral agents.”

Research that is complete and has resulted in approval by the European Commission in 2008 of two new oral anticoagulant - dabigatran etexilate (Pradaxa), a direct thrombin inhibitor, and rivaroxaban (Xarelto), a direct inhibitor of coagulation Factor Xa - is prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients who have hip replacement and knee replacement surgery.

“This is a very important area because more and more people are getting old and more people are getting degenerative joint disease, and require surgery to correct what are effectively ‘mechanical disorders’, which are preventing them from any normal lifestyle,” says Prof Turpie. “The problem is that these operations are major and are associated with a risk of thrombosis, and as a result there are recommendations to give these patients anti-coagulant drugs.”

Venous blood clots occur in 40 to 60 percent of patients undergoing major orthopaedic surgery who do not receive preventive care.

“Now we have new drugs that target single coagulation factors and have lots of practical advantages over the current drugs. They are given by mouth - rivaroxaban is once a day, the others are twice a day - without the requirements of monitoring. So you can see the big advantage practically.

“The big question is do they work? Well, we can look at the clinical trials to see that they do. Both of them are approved for use in Ireland. Dabigatran has not got as strong data as rivaroxaban. It has been tested in three phase III clinical trials against low molecular weight heparin, two of them show non inferiority with LMWH and the other one failed to show non-inferiority, so there is mixed data with dabigatran. Despite that, the overall data set indicates probable clinical equivalence.

“Rivaroxaban, on the other hand, has had four clinical trials – this is the RECORD programme that I’m involved in – and showed superiority over LMWH. So not only was it equivalent, it was better. Further more, when one looks at the totality of the Rivaroxaban data there is a reduction of symptomatic thrombosis and mortality. So this is a new finding. Now we have hard evidence that we can reduce symptomatic thrombosis and mortality and that’s a big advantage.”

The soft-spoken Scotsman is eager to address a key issue raised by many who have been awaiting these research findings: is this benefit associated with more bleeding?

“In clinical trials statistically there was no difference with bleeding but when you do the composite of all of them there is a trend towards more bleeding, and that doesn’t surprise me if you’ve got a very potent anti-coagulant given early that there will be a little more bleeding. But overall the net clinical benefit is quite dramatic and I think that out weights any possible adverse effect,” he explains.

Indeed, an Advisory Committee of the US Food and Drug Administration (FDA) issued a favourable review of rivaroxaban on 19th March after examining a number of scientific and clinical questions in relation to the new drug application. At the time of going to press, the FDA was expected to announce its final decision in relation to rivaroxaban’s application in the USA for the prophylaxis of DVT and PE in patients undergoing hip or knee replacement surgery. Again, Prof Turpie voices his optimism: “Based on the recommendation by the expert panel, they should give it approval.”

He is quick to add that these new oral anti-coagulants are also being tested across the spectrum of thrombobolic disease with initial indications pointing to very positive outcomes.

“Dabigatran, for example: data on its application in atrial fibrillation will be available in the Fall of this year when it is presented at the European Society of Cardiology. That’s a study called RE-LY,” he notes.

The Phase III Randomised Evaluation of Long term Anticoagulant therapy (RE-LY) study enrolled more than 18,000 patients in over 900 centres in 44 countries worldwide between December 2005 and December 2007. Investigators compared the efficacy and safety of two blinded doses of dabigatran etexilate with open label Warfarin for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

“The study with rivaroxaban - called ROCKET AF: Stroke prevention in patients with atrial fibrillation (Phase III) - is almost finished it’s enrolment but will not be completed until next year.

“There are differences in the clinical trials so there will be slightly different outcomes I believe, we’ll have to wait to see the data, but suffice it to say I think both of them will work in atrial fibrillation,” Prof Turpie adds enthusiastically. “They will make a treatment for the prevention of stroke much simpler in atrial fibrillation and that has the potential to abolish a million strokes a year worldwide. That’s big thing: a massive step forward.

“About one-fifth of all strokes are related to atrial fibrillation, and we know that we can reduce that risk by about 70 percent with anticoagulation therapy, perhaps even more with these new agents. You can imagine the advantage to all of us physicians and health professionals and patients alike if we have a simple way of administering anticoagulants.”

He stresses that there is an enormous unmet clinical need in this area. More than 6 million worldwide have atrial fibrillation and 15 percent to 20 percent of strokes occur in people with this disorder, he remarks.

In addition, the likelihood of developing atrial fibrillation increases with age – 3 to 5 percent of people over 65 have AF. The elderly are also more likely to be taking multiple medications and may have dietary problems.

“So the whole issue of being able to give a fixed dose regimen and a drug that has very few drug interactions or food interactions could be a huge advantage.

“These are all very exciting developments, particularly when you think that for decades we’ve only had Warfarin, but now there is this exciting new potential for choice.”

Each milestone in the evolution of anti-coagulation therapies are landmarks in a personal journey for Prof Turpie, who has committed himself to ongoing investigations in this area for more than four decades, publishing more than 700 articles, abstracts, book chapters, and books.

He holds a medical degree from the University of Glasgow, Scotland, and after completing residencies at the Royal Infirmary and Stobhill General Hospital, Glasgow, where he was also a clinical research fellow, he served as a clinic lecturer for the University of East Africa Medical School in Nairobi, Kenya. During this time he served as a flying doctor with the East African Flying Doctor Service.

“We started doing experiments with snake venom and we found that some of them had anti-coagulant properties and some of them had pro-coagulant properties. Now it was very unsophisticated in those days but it was a very interesting observation, you know, the way that some of these snakes abolished their pray by making them bleed to death and others made them clot. I am pretty certain that a lot of the advances and understanding of coagulation is based on what these venoms used to do to coagulation, and some of them have resulted in therapeutic advances,” he reflects.

After returning to the University of Glasgow for additional training in haemostasis and thrombosis, he was appointed an MRC fellow at McMaster University in Ontario, Canada, where he was also appointed to the full-time faculty in the Department of Medicine. He is now professor of medicine and also an internist on the staff of Hamilton Health Sciences in Ontario.

“I’ve been around for a while and I’ve been lucky enough to see a lot of interesting advances, but I do believe that one of the most important things in anticoagulant therapy will be a revolution in oral anticoagulants, and that will be with a replacement for Warfarin,” Prof Turpie says. “Patients and healthcare providers alike have all been anxiously awaiting something that will take over from Warfarin. Make no mistake, Warfarin is a good drug; it’s an effective drug but it has major problems from a practical point of view.

“If we can have a drug that is as good as Warfarin in terms of it’s effectiveness and is safe and simple to take then there is going to be a revolution.”

VENUS THROMBOEMBOLISM (VTE)

• The estimated total number of symptomatic VTE events in the European Union (EU) is in excess of one million each year
• VTE is the third most common type of cardiovascular disease
• VTE causes over 500,000 deaths in Europe every year.
• Deaths attributable to VTE are estimated to exceed the total combined number of deaths from breast cancer, prostate cancer, AIDS, and traffic accidents annually.
• About one in eight patients will die as a result of a venous blood clot that develops while in the hospital.
• The number of in-hospital deaths due to VTE is five times the total number of deaths from all hospital-acquired infections.
• Hospitalised patients and residents of nursing homes account for about 60% of all cases of VTE.
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Atrial fibrillation (AF)

• An estimated 2.2 million people in the US and 4.5 million in the EU have atrial fibrillation.
• The risk for stroke (for patients with AF) is age-dependent. In the Framingham study, the annual risk was 1.5 percent in those 50 to 59 years old and 23.5 percent in those 80 to 89 years old.
• Atrial fibrillation is the most common arrhythmia seen in clinical practice.
• For men 55 years of age, the lifetime risk for developing atrial fibrillation is 25 percent: for women 55 years old, the risk is 22 percent
• An estimated one in every six strokes occurs in a patient with atrial fibrillation.