New and forthcoming oral anticoagulants, which do not require prothrombin time monitoring, will offer patients and providers additional therapeutic options.
Due to warfarin’s (Coumadin and generics) narrow therapeutic index and the need for routine coagulation monitoring that leads to dosage adjustments, therapeutic alternatives to this longtime standard of care have been widely anticipated.1 Recent entrants into the oral anticoagulant class have given patients and providers additional therapeutic options. The newest oral anticoagulants to come to market are Pradaxa (dabigatran) and Xarelto (rivaroxaban). Unlike warfarin, the most commonly prescribed oral anticoagulant, these newer oral anticoagulants do not require prothrombin time monitoring using international normalization ratio (INR) parameters to determine the clotting tendency of blood.2-5
Keeping the INR in the therapeutic range can be a difficult and expensive process for some patients. If the INR is too high, risk of bleeding increases; if it is too low, there is an increased risk of stroke. British researchers with the Center for Evidence-Based Medicine at the University of Oxford have reported that patients taking warfarin who are able to monitor their own blood and adjust their dosage can reduce the risk of blood clots by half, but at a substantial cost that may offset much of the economic advantages from using the older, less expensive drug.6 Self-monitoring of warfarin involves use of a meter similar to those diabetics use for blood sugar testing. In this case, patients place a drop of blood from a finger prick on a test strip and insert the strip into the device, which reads the INR. The INR monitors cost $1500 to $2500, and strips can run from $7 to $18 per test, according to the National Blood Clot Alliance.7 Insurance coverage depends on the payer and the condition for which warfarin is being used.
While the Oxford-based researchers found that selfmonitoring reduced the risk of stroke or deep vein thrombosis by 49% compared with the standard care involving physician-conducted blood testing, it did not signifi cantly alter the odds of a major bleed or death.6 Of the 3 million Americans currently on warfarin, only about 1% conduct self-monitoring of their INR.8
In October 2010, the US Food and Drug Administration (FDA) approved Pradaxa, a direct thrombin inhibitor, to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.9,10 One of the benefits claimed for Pradaxa compared with warfarin is a short half-life in patients without renal dysfunction, which equates to both a quick onset and offset of action.9,11 The safety of Pradaxa, however, may be compromised in certain clinical situations, such as its use in patients with renal impairment, patients undergoing invasive procedures, and patients exposed to neuraxial anesthesia techniques.12 Additionally, Pradaxa, unlike warfarin, has no pharmacologic antidote to reverse/counter the effects of the drug—which may be problematic in situations where rapid reversal of anticoagulant therapy is required (eg, acute hemorrhagic complications or emergent invasive procedures).13
Recent reports present growing evidence that Pradaxa may be associated with a signifi cant number of serious adverse events. According to the QuarterWatch report published by the non-profi t Institute for Safe Medicine Practices, there were 505 cases of Pradaxa-associated hemorrhage reported to the FDA in the fi rst quarter of 2011, more than for any other drug. By way of context, warfarin ranked second with 176 cases. These cases resulted in serious outcomes including death, disability, or hospitalization.14 In addition, a meta-analysis of 7 clinical trials published in the Archives of Internal Medicine online edition during January 2012 found Pradaxa was “significantly associated with a higher risk of heart attacks and acute coronary syndrome than that seen with agents used in control arms which included warfarin, enoxaparin, or placebo.”15 The growing evidence of a Pradaxa link to serious adverse events could provide a competitive advantage for rival drug Xarelto.
Approved in July 2011, Xarelto is a factor Xa inhibitor that carries the following indications: to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (the atrial fibrillation indication was approved in November 2011), and for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in patients undergoing knee or hip replacement surgery.16 Xarelto is dosed once daily, while Pradaxa is dosed twice daily— the more convenient dosing schedule would appear to be a commercial advantage for Xarelto.17 Xarelto has a boxed warning to highlight the risks of discontinuing treatment in patients with nonvalvular atrial fi brillation as well as the possibility of spinal/epidural hematoma.16
Atrial fibrillation (AF) affects more than 2 million Americans and is one of the most common types of abnormal heart rhythm. The prevalence of this condition is anticipated to increase signifi cantly over the next few decades as the US population ages.10,18-20 In fact, it is estimated that as many as 12 million people will have AF by 2050. The cost of treating AF is significant. In 2005, the estimated cost of treating AF was $6.65 billion per year, including the costs of hospitalization, in- and outpatient physician care, and medications.2,21 The 2 most common complications of AF are stroke and heart failure, with AF responsible for 15% to 20% of ischemic strokes.21
To determine the switch rate among the oral anticoagulants and to look at utilization of these agents by age band.
This retrospective analysis was conducted using the CVS Caremark Trend cohort, excluding Med-D for YTD September 2011. This retrospective analysis was conducted using prescription claims from the CVS Caremark computerized database. The following agents were included in our analysis: warfarin (generic and brand forms), Xar elto, and Pradaxa. The switch analysis was done by looking back from September 30, 2011, to fi nd the anticoagulant agent prior to the last therapy. If no agent was found in 2011, the patient was determined to be a “new utilizer” of anticoagulant therapy— otherwise, the last anticoagulant agent was determined to be the agent that the member had “switched” from.
A retrospective claims analysis was done using the CVS Caremark Trend cohort for employer and health plan clients, which represents 28 million lives. To be included in the trend cohort, clients must have had stable (not to exceed +/- 20%) membership for at least 2 years, with continuous claim activity over a period of at least 24 months. Looking at data for YTD September 2011, there were 80,373 Pradaxa utilizers, 391 Xarelto utilizers, and 756,727 warfarin utilizers. The cost per claim was much greater for Pradaxa comparatively (Table 1).
As shown in
, the majority of utilization across all 3 products falls within the 45 to 64 and 65+ age groups. Interestingly, only 33 percent of Xarelto users fall into the 65+ age band, while Pradaxa and warfarin users of that age represented 73.5 and 63.9 percent of total utilizers respectively.
Looking at the switch rate among the oral anticoagulants (
), we see that the majority of patients switching from a warfarin product to a newer oral agent are switching to Pradaxa. Additionally, the vast majority of patients new to any anticoagulant therapy that chose to use a newer oral anticoagulant are using Pradaxa over Xarelto. There are also many utilizers who switched from Pradaxa to a warfarin product—which could signal issues of tolerability or safety concerns.
The new oral anticoagulants offer improved patient convenience since regular coagulation monitoring is not needed. However, for some patients and clinicians, a monitored oral anticoagulant may be preferable.
There are a number of oral anticoagulant agents in the pipeline, and one product currently under FDA review receiving a lot of attention is Eliquis (apixaban).17 Additional oral anticoagulant agents in the pipeline include: semuloparin, a Factor Xa inhibitor/thrombin inhibitor which is anticipated to launch in the third quarter of 2012; edoxaban, a Factor Xa inhibitor that is anticipated to launch in 2013; and betrixaban, a Factor Xa inhibitor with an unspecifi ed projected launch date.22
The availability of oral anticoagulants which do not require coagulation monitoring is a signifi cant advancement in patient care. However, the place of these agents in day-to-day clinical practice has yet to be solidifi ed. As additional oral anticoagulants enter the market, this class will continue to grow and will continue to play a larger part in drug trend since these newer agents are significantly more expensive than traditional warfarin therapy.