Future Medicine is a new section of Clinical Correlations devoted to hot areas of research and development in various fields of medicine. In tihis series, we will highlight treatments in their infancy, from basic research opening up new targets for treatment, to following small molecules throughout their clinical investigation. We will also bring you the latest on technology and devices, as well as perspectives on drug discovery from a business point of view. Watch out – the future is just around the corner!
Commentary by Aaron Lord MD, PGY-1
We have all been there before: a patient sitting in front of you, be it in clinic, the ER, or as an inpatient, with newly diagnosed atrial fibrillation (AF), and it’s up to you and the patient to decide on a plan for anticoagulation. With an aging population, AF has not only become more prevalent, but the decision of whether to anticoagulate has become more difficult – Can my patient reliably take Coumadin everyday? Can they understand the complex and changing dosing? Will they follow-up in Coumadin clinic? All of the pitfalls of Coumadin therapy have driven a number of pharmaceutical companies to develop new forms of anticoagulation that have far less drug-drug and drug-food interactions and do not require frequent INR checks. We will quickly review the necessity of anticoagulation in atrial fibrillation and then take a look to see if any of the new drugs compare favorably to the efficacy and safety profile of that old workhorse Coumadin.
With medicine’s renewed emphasis on evidence-based practice, it is important to review the necessity of anticoagulation in AF. The well-known goal of anticoagulating patients with AF is prevention of clot formation in the left atrium (and most importantly in the left atrial appendage), thus preventing systemic thromboembolic disease, most importantly, strokes. Although Coumadin was developed in late-1940s, large-scale randomized-controlled trials (RCTs) were not done until the late 1980s, but with impressive results. The relative risk reduction of ischemic stroke provided by Coumadin in the primary prevention trials ranged from 52-86%, and when you consider the reported annual 3.0-7.4% incidence of stroke, that is a significant absolute risk reduction. In other words, for roughly every 20 to 40 of you patients with AF on coumadin, you will prevent one of these patient’s first stroke, every year. The results are even more impressive for secondary prevention, a 12.3% annual risk of recurrent stroke is reduced to 3.9%, so you only need to treat 12 patients to prevent one recurrent stroke every year.
Knowing that anticoagulation with coumadin is effective but difficult, pharmaceutical companies have been developing new anticoagulants based on different targets other than Vitamin K inhibition. As aggressive platelet inhibition (aspirin/plavix) has now been proved inferior to coumadin (ACTIVE-W), drug development has focused on two new major classes of coagulation enzyme inhibtion: oral direct thrombin inhibitors (DTIs) and oral and long-acting parenteral factor Xa inhibitors.
DTIs works on the common final pathway of both the direct and indirect coagulation cascades, preventing thrombin from converting fibrinogen to fibrin. DTIs come in two flavors : univalent and bivalent. Bivalent DTIs are synthetic derivatives of hirudin, the naturally occurring anticoagulant found in the medicinal leech, and therefore have names ending with -rudin. IV forms, such as bivalirudin (Angiomax) are already used during percutaneous coronary interventions (PCI) and have been studied in treatment of ACS. Univalent DTIs have been made famous by the star of the class, argatroban, used in treatment of heparin-induced thrombocytopenia (HIT), although this too is only available in the IV form.
Success in these fields has led to the development of oral univalent DTIs, the first two being ximelagatran and dabigatran. In the randomized-controlled SPORTIF trial, ximelgatran was found to be non-inferior to warfarin in the prevention of stroke in AF and resulted in less bleeding complications. However, 6% of patients receiving ximelgatran had a greater than three-fold increase in serum alanine aminotransferase (ALT) levels, with two patients dying of liver disease, and the drug failed to receive FDA approval. Its sister-compound, dabigatran, is undergoing a large randomized-controlled trial (RELY), and early studies show non-inferiority to Coumadin in primary prevention of stroke in AF (PETRO) and Lovenox in prevention of DVT after orthopedic surgery (RE-MODEL and RE-NOVATE). Importantly, these studies showed no significant difference in ALT elevation compared to warfarin or enoxaparin groups and no fatal liver disease was observed. If you’re thinking dabigatran might be the next oral anticoagulant and would like to invest, try again, the developer is Boehringer Ingelheim, a family-owned German pharmaceutical manufacturer with a large Connecticut presence.
Another large class of anticoagulants being developed are factor Xa inhibitors. Factor Xa is the convergance point of the intrinsic and extrinsic clotting cascades, thus providing the most robust, ie, upstream, target for anticoagulation of both systems. Older drugs in this class, such as idraparinux and fondiparinux, are parenteral and rely on interaction with anti-thrombin III for their effect. A recent large scale RCT (van Gogh) showed once weekly subcutaneous injection of idraparinux to be non-inferior to warfarin in the prevention of recurrent DVT, but inferior for prevention of recurrent pulmonary embolism. An extension of that trial went on to show increased rates of bleeding in the idraparinux group, however. A more recent trial (AMADEUS), brought even more devastating news for the drug, as the trial had to be terminated early due to a significantly increased risk (50%) of major bleeding, especially intracranial bleeds (200%) , when compared to the Coumadin group. A significant amount of this risk was concentrated in elderly patient with renal failure, so the possibility of an improved safety profile with more precise dosing awaits investigation.
Despite the current troubles of idraparinux, drug development continues in the search for a safe and effect oral Xa inhibitor. The drugs do not require binding with anti-thrombin III to mediate their activity and can thus inhibit factor Xa in the bloodstream and in clots themselves. Phase II and III trials are underway for at least 7 other drugs in this class—notably Bristol Meyer Squibb’s apixaban and Bayer’s rivaroxaban—so be on the lookout!
Albers GW, et al. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA. 2005 Feb 9;293(6):690-8.
Eriksson BI , et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial.
J Thromb Haemost. 2007 Nov;5(11):2178-85.
Eriksson BI, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet. 2007 Sep 15;370(9591):949-56.
Ezekowitz MD, et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol. 2007 Nov 1;100(9):1419-26. Epub 2007 Aug 17.
Savelieva I, et al. Stroke in atrial fibrillation: update on pathophysiology, new antithrombotic therapies, and evolution of procedures and devices. Ann Med. 2007;39(5):371-91.
One comment on “Future Medicine: The Search for a New Anticoagulant”
Grand Rounds today offered an outstanding summary of where pharmacogenomics is today and one of the best real-life examples was that of warfarin. In August, 2007, the FDA changed its labeling of warfarin to reflect the following http://www.fda.gov/cder/drug/infopage/warfarin/qa.htm
•People with two genetic variations in the genes, CYP2C9 and VKORC1 may need lower warfarin doses than people without these genetic variations. The CYP2C9 gene is involved in the cytochrome P450 system and the VKORC1 gene helps regulate vitamin K metabolism
•Tests for these genetic variations are currently available, though not required
•It has been estimated that individuals with the CYP2C9 gene variants may be as high as 10% to 20% in Caucasians and African-Americans while the frequency of VKORC1 is estimated at 14% to 37%. The frequency of this latter genotype in the Asian population may be as high as 89%.
Thus, we may be close to a time when the assessment of a patient initiating warfarin will require knowledge of the presence of the genetic variations known to be associated with higher bleeding risks. You may see the following in the not-to-distant future:
The pt is a 54 year old female with new onset atrial fibrillation. The patient’s genomics profile revealed the CYP2C9*2 variation and thus, she will be started on 3 mg of warfarin a day.
So, while Dr. Lord presents some interesting data on the development of new anticoagulants, it is important to understand that the growth of pharmacogenomics and “personalized medicine” may achieve the desired outcome of increased safety in the drugs we have available for use.
Time will tell.
Schwarz UI et al. Genetic Determinants of Response to Warfarin during Initial Anticoagulation. N Engl J Med 358:999, March 6, 2008.
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