Apixaban, brand name Eliquis, is expected to gain FDA approval by the end of 2011 and is likely to become the most widely used of these drugs because of what appears to be not just non-inferiority to warfarin but superiority in major outcomes. Apixaban will join Pradaxa and Xarelto among the novel new anticoagulant drugs that can be used as an alternative to warfarin for patients who need potent drugs to prevent blood clotting in disorders like atrial fibrillation and deep vein thrombosis of the legs. Apixaban, to be marketed by Bristol-Meyers Squibb and Pfizer as Eliquis seems to be possibly the most exciting of these drugs so far. In a study of over 18000 patients with atrial fibrillation called the ARISTOTLE Study apixaban was the first of the drugs to show statistically significant superiority to warfarin in the key endpoints of incidence of bleeding complications (31% lower), risk of stroke (21% lower) and risk of death (11% lower). Showing superiority vs. warfarin is going to be a key to successful marketing of these drugs because the generic warfarin is widely available and strongly entrenched in the marketplace. All of these new drugs are going to be expensive, and in order to achieve widespread use they will need to prove superiority in both safety and efficacy.
All of the drugs released so far work as direct inhibitors at one point or another in the coagulation cascade, unlike warfarin which as a vitamin K antagonist works by reducing the production of key clotting factors. Apixaban and Xarelto are factor Xa (X as the Roman numeral for 10, and “a” for activated) inhibitors, and Pradaxa is a direct thrombin inhibitor. They are immediately active in their functional roles after being absorbed from the gut, and so the speed of action of these drugs is much faster than the speed of action of warfarin. This is likely to play a key role in looking at the overall cost of use of these drugs. Warfarin use requires several days to take effect, and the necessary dose is highly variable. From significant personal experience I can say that when quick anticoagulation is needed as in DVT management there are two major drawbacks to warfarin use. First it is necessary to treat patients with heparin initially in order to get prompt anticoagulation. Secondly it is very common to take a week or more to achieve therapeutic levels of anticoagulation. Often the initial dose chosen is either too high or too low. The prothrombin time, or more commonly the INR, is used to measure the degree of anticoagulation with warfarin. Dosing of warfarin can be anywhere from <1 mg daily to 15 mg daily, and is difficult to predict. It is not uncommon to have patients significantly over anti-coagulated a week after starting warfarin requiring that the dose be reduced, only to then to reduce the dose and a few days later find that they are now significantly under anti-coagulated. This yo-yo effect necessitates frequent INR monitoring and visits to have INR testing. Essentially all of the new drugs work within one to two days, and are twice a day dosed because of relatively short half-lives. Although twice daily dosing may seem a drawback due to patient compliance issues (vs. once daily warfarin dosing), I see it a potential benefit because its corollary is that the drug will be out of the system quickly so that any bleeding complications will likely be short lived when they do occur.
Warfarin can be reversed with vitamin K or fresh frozen plasma, but the use of vitamin K takes at least a couple of days, and use of fresh frozen plasma exposes patients to human blood product risks. I see the faster onset and faster loss of efficacy of apixaban and Pradaxa as significant benefits.
This combined with superiority in three major measures of efficacy and safety for apixaban make it likely that when this drug is approved for use in the U.S. that it will become a very popular new drug. Pradaxa is already gaining traction among cardiologists in stroke prevention in atrial fibrillation patients, but I suspect that unless Pradaxa can show superiority rather than its current “non-inferiority” claims to warfarin that apixaban may quickly gain favor among physicians and patients. Another drug rivaroxiban is already on the market in Europe and has shown non-inferiority to warfarin in stroke prevention, superiority in bleeding risk, but did not improve overall survival in comparison to warfarin.
|apixaban vs warfarin||Pradaxa vs. warfarin||rivaroxiban vs warfarin|
|Lower risk of Strokes in a-fib||Possibly Lower risk of Strokes in a-fib||Non-inferiority re Stroke prevention in a-fib|
|Lower risk of Bleeding||Mixed data on risk of Bleeding||Lower Risk of Bleeding|
|Lower mortality||No mortality data||No reduction in mortality|
Apixaban is in phase three clinical trials and is expected to receive FDA approval by the end of 2011. Some market analysts anticipate that apixaban may end up the overall winner in the competition for the leading position among the new anticoagulant drugs. I suspect that they are correct because to this point only apixaban can claim significant superior efficacy and safety in comparison to warfarin. I expect warfarin use to be significantly impacted because in addition to the increased efficacy and increased safety, its use eliminates the need for INR monitoring. The real question is going to be whether the first-to-market advantage of Pradaxa is enough to hold off apixaban, and whether insurance companies perceive there is an overall cost benefit to paying for the new drugs.
Another issue is that Pradaxa is only approved for use in non-valvular atrial fibrillation for stroke prevention, and Xarelto is only approved at this time for post-operative DVT prevention in total joint replacement patients. It is likely that apixaban will only get an indication for stroke prevention in non-valvular atrial fibrillation. I expect wider indication approvals to be forthcoming for this class of drugs as there is little reason to expect that they will not also work for therapy of DVT and DVT prophylaxis in hypercoagulable states. Stay tuned to see if apixaban gains the popularity that some predict it is destined to have.