When a medicine is launched you know about 50% of what you need to know, the other 50% comes from somewhere after you have launched the medicine. That's a quote from Patrick Vallance President of Pharmaceuticals R&D at GSK speaking at a recent Academy of Medical Sciences meeting. This type of comment is not what you would normally expect to hear from a pharmaceutical company. Usually the representatives quote the research and development and the pivotal clinical trial as if the totality of knowledge was available when the drug is introduced.
The launch of the new oral anticoagulants (NOAC) represents an important milestone in cardiovascular therapeutics. The pharmaceutical industry is changing and the old models of trying to discover a blockbuster drug is probably not going to work. But the NOACs are part of this old model where a replacement for warfarin is highly likely to be a blockbuster. Once a new medicine has moved from pre-clinical to clinical development, passed the phase 3 clinical trial testing and been shown to be effective it is over to the marketing division to ensure that the drug is as successful as possible. At that point maximising the return on investment over the final years until the patent expires is the most important job.
Dabigatran was the first NOAC launched as a replacement for warfarin. The RELY trial demonstrated that dabigatran was at least as effective as warfarin at reducing the risk of ischaemic stroke in people with atrial fibrillation. However since its introduction into clinical practice the rates of bleeding and unwanted effects of the drug appear to be much higher than those reported in the original clinical trial raising concerns from the FDA. Take a recent paper in 467 consecutive Chinese patients in atrial fibrillation. They were a typical mix of patients older people who had a CHA2DS2-VASc score of 3.6 and therefore an annual stroke risk of about 3.5-4%. They were prescribed dabigatran for stroke prevention. Over the subsequent 16 months of follow up one fifth of people permanently discontinued the drug. One third of people stopped it because of indigestion symptoms followed by other adverse events such as minor bleeding (9%), major gastrointestinal bleeding (8%), and intracranial hemorrhage (1%). In the patients on the drug there were 9 ischemic strokes, 3 intracranial bleeds and 24 major gastrointestinal bleeds. So in this population the annual stroke risk without anticoagulation would be predicted from the CHADS2VASC score to be about 3.8% the observed 5.8% risk of intracranial and gastrointestinal bleeding is a cause concern as is the very high rate of discontinuation of the drug.
Dabigatran has been promoted as much simpler and more convenient for patients than warfarin because the manufacturers say that they there is no need for blood monitoring. However a study published in JACC earlier this year showed that there was very high degree of variability in the plasma levels of dabigatran in patients. Those people with high plasma levels of dabigatran not surprisingly had a higher risk of bleeding and this has led some people to ask whether monitoring of plasma levels might improve the safety profile of the drug.
Probability of Major Bleeding Event and Ischemic Stroke/SEE Versus Trough Plasma Concentration of Dabigatran Calculated for 72-year-old male atrial fibrillation patient with prior stroke and diabetes. Lines and boxes at the top of the panel indicate median dabigatran concentrations in the RE-LY trial with 10th and 90th percentiles.
Only time will tell as we get a more complete picture of the clinical pharmacology and real world experience of using the NOACs but like all new drugs we should exert a degree of caution and remember that we only know about half of what we need to know when the drug is launched.
Dr Richard Bogle
The opinions expressed in this blog are strictly those of the author and should not be construed as the opinion or policy of my employers nor recommendations for your care or anyone else's. Always seek professional guidance instead.