Coagulation disorders – advances in treatment confirmed

[17 November 2010 - 11h55]
[mis à jour le 19 November 2010 à 14h03]

Every year, three million people fall victim to a CVA (cerebrovascular accident or stroke) due to atrial fibrillation, the most common cardiac rhythm disorder. Half die within a year. Deep vein thrombosis, for example associated with post-operatory phlebitis, also claims hundreds of thousands of victims.

The reference treatment for such conditions is warfarin which has a proven track record over many years. However, this drug requires meticulous adjustment, repeated blood tests and a strict dietary regime. At the American Heart Association meeting in Chicago, two alternative drugs have been put forward that are as or more effective, more manageable and better tolerated than warfarin – they represent the first major innovation in 50 years. And what if, on top of all this, they were also more economical?

There are around 2 million people on warfarin in the United States. In France the number is estimated at between 600,000 and 800,000. This antivitamin K treatment (AVK) has been known for many years but any overdose can lead to haemorrhagic disorders. Its use therefore requires restrictive and very costly monitoring.

Too many therapeutic accidents

A study carried out in France (the EMIR study, which stands for National Study on Serious Treatment-linked Undesirable Events has confirmed that these anticoagulants were the cause of 12.3% of hospitalisations due to therapeutic accidents. This represents almost 4% of hospitalisations in France. A monitoring diary for patients treated with AVK has in fact been developed by the AFSSaPS (France’s Health Products Safety Agency).

The two new drugs are administered orally, which is important for observance of treatment. And as Professor Noël Milpied (of Bordeaux Haut-Lévèque University Hospital) explained last December, there are most definitely “changes in practice in sight”. Indeed these drugs offer a safety profile at least as good as warfarin … but without its disadvantages?

Their modes of action are different. Dabigatran (Pradaxa in Europe) is the first thrombin inhibitor – thrombin being the enzyme essential to clot formation. Already used to prevent thrombosis following total hip prosthesis, its use has now been extended to prevention of cerebrovascular accidents (CVAs) in cases of atrial fibrillation. A study of 18,000 patients in 44 countries (the RE-LY study) has indeed demonstrated its potential against cerebral infarction.

Among these patients, with an average age of 72, monitored over two years, the researchers observed “a significant reduction in the number of CVAs (compared with patients treated with warfarin, ed. note) with a lower bleed rate, including bleeds involving vital prognosis and intracranial haemorrhages”. Professor Stuart Connolly (of Mac Master University, Hamilton, Canada), believes this 35% improvement, with only 21% treatment withdrawal, to be decisive. “For our patients, it is very important to have a more effective, safer treatment available that is easier to use”, he explained.

Recently authorised by the American Food and Drug Administration (FDA) and by Santé Canada, this drug therefore establishes a new reference treatment.

Rivaroxaban, also used in the long-term prevention of recurrent thrombophlebitis, in particular after knee and hip replacement operations, acts on another coagulation factor known as factor Xa. In the near future application could also be made to extend marketing authorisation of this drug to the prevention of CVAs and other complications of atrial fibrillation.

Two irons in the fire ?

A new study (ROCKET-AF) has also recently shown that rivaroxaban too appears to be as effective as warfarin, but without the latter’s disadvantages. More than 14,000 patients with an average age of 73, recruited in 45 countries, took part in this study. The relative risk of non-neurological CVAs and embolisms was reduced by 21% compared with warfarin. There was actual reduction in mortality, all causes taken together, but this was judged to be “statistically insignificant” by the authors. Even with just over 32% of patients lost from sight due to withdrawal of treatment, this new approach still represents a significant way forward. Its “global safety profile still lacks clarity” according to Dr Elaine M. Hylek of Boston University School of Medicine, but these first results “are very interesting”. And the study’s principal author, Dr Robert M. Califf (of Duke University, Durham, United States) believes that “we have here an alternative to warfarin”.

Two in fact, one might say. These new drugs will now be asked to prove their worth. Aside from issues of pure effectiveness and safety, which already appear to be being addressed , the debate also revolves around the economic aspect. A study conducted in Palo Alto (California) published a few days ago considers that dabigatran is “at least as effective, and perhaps even more so, than warfarin. But the question that remains is whether its use is economically viable.” Dr Mintu Tutakhia, an inspector with the Veteran’s Administration, has hit the nail on the head. His organisation is responsible for meeting former combatants’ healthcare costs. In collaboration with the American Heart Association, the organisation therefore commissioned a study that “modelled” the relative cost-effectiveness of treatment with warfarin and with dabigatran.

More expensive but requiring less costly monitoring, this new drug appears to have its hat well in the ring. But not at any price. Dr Tutakhia has, for example, publicly set the threshold beyond which the use of this new drug would no longer be viable … for the Health Insurance authorities. No doubt this new drug duel will be carefully followed, and on both sides of the Atlantic, of course.

For more information: Treatment with AVK: the AFSSaPS’s 7 golden rules http://www.afssaps.fr/var/afssaps_site/storage/original/application/908d294c4ff121207ee1436de24666dd.pdf

Source : from our special correspondent at the 2010 Scientific Sessions of the American Heart Association (AHA), Chicago, 14 -17 November 2010 - New England Journal of Medicine 361, published online 30 August 2009. RE-LY study (Randomized Evaluation of Long-term Anticoagulant therapy) - New England Journal of Medicine 363, 19, 4 November 2010 - Stanford University School of Medicine & Veterans Affairs Palo Alto Health Care system, 1st November 2010 – ROCKET-AF Califf, R et al "Stroke Prevention Using the Oral Direct Factor Xa Inhibitor Rivaroxaban Compared With Warfarin in Patients with Nonvalvular Atrial Fibrillation" AHA 2010 – interview with Dr Stuart Connolly, 15 November 2010.

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