With the advent of the novel oral anticoagulants, a major change in the stroke prevention in atrial fibrillation (SPAF) market was heralded. Thought leaders were predicting the end was nigh for warfarin; no more INR monitoring, no more dose adjustment to maintain time in therapeutic range (TTR) the idea was that rat poison would be used to poison rats and not much else. I have written previously how warfarin is proving remarkably resilient within the SPAF market. Prescription data within the United States reveals that warfarin is still capturing as much of 35 percent of first-time prescriptions for an anticoagulant. However, for the first time, warfarin is no longer the leader among first-time prescriptions. The surprise is perhaps which agent has supplanted warfarin as the prescription leader: rivaroxaban (Bayer/Janssen's Xarelto).

Each of the three novel oral anticoagulants that have come to the SPAF market underwent large-scale Phase III clinical trials, with all three agents underwent a trial with warfarin as the comparator. In the ARISTOTLE trial apixaban (BMS/Pfizer's Eliquis) demonstrated superiority over warfarin for stroke reduction, bleeding and mortality, which appears on the product label. Neither rivaroxaban nor dabigatran etexilate (Boehringer Ingelheim's Pradaxa) can match this on their product labels. Some argue that differences in the design of the clinical trials for each of the agents mean that attempting to compare these agents is comparing apples and oranges (or perhaps red apples and green apples). For example, patients in the ROCKET-AF trial for rivaroxaban had a higher CHADS2 score (an indicator of stroke risk). Yet the TTR of warfarin-treated patients in the ROCKET-AF trial was a rather low 55 percent. The failure of rivaroxaban to demonstrate superiority over relatively poorly anticoagulated warfarin-treated patients was thought not to bode well, a factor that was referenced in a briefing document to the FDA's Cardiorenal Advisory Committee. However, rivaroxaban did gain FDA approval in November 2011.

Interestingly, BMS and Pfizer undertook the somewhat risky decision to perform the additional AVERROES trial in which apixaban was compared to aspirin in patients ill-suited to warfarin therapy. The decision paid off, with the trial being terminated prematurely due to the clear superior efficacy of apixaban without any increase in bleeding risk. Based on this data, in addition to that of the ARISTOTLE trial, apixaban was widely forecast to become the future market-leading anticoagulant for SPAF.

However, following its launch in the United States in Q1 2013, Q2 sales of $12 million fell well short of estimates. So the question is how does a drug with apixaban's label lose out to rivaroxaban and perform so poorly following launch Within the cardiovascular space, a recent precedent for apixaban can be seen within the ACS market and ticagrelor (AstraZeneca's Brilinta). Despite clear superiority over clopidogrel (BMS/Sanofi's Plavix), clopidogrel continued to dominate the ACS market, with ticagrelor falling below all expectations. So how can BMS/Pfizer avoid the fate of ticagrelor, which may potentially face a re-launch in order to kickstart its thus far flagging fortunes.

BMS and Pfizer have quickly acknowledged that they have not been aggressive enough in marketing apixaban, which was also a major fault following the initial launch of ticagrelor, and has been a major factor in the success-to-date of rivaroxaban. Bayer and Janssen have been aggressive in the marketing of rivaroxaban, which has translated into over 39 percent of new prescriptions among cardiologists (compared to 16 percent for apixaban, and 12 percent for dabigatran). BMS and Pfizer's lackadaisical marketing of apixaban has translated into poor hospital formulary relisting and stocking, which depreciated Q2 sales. Bayer and Janssen have also maximized awareness of two key advantages of rivaroxaban over apixaban. The once-daily dosing of rivaroxaban compared to the twice-daily dosing of apixaban is quoted by physicians surveyed by Decision Resources as an important consideration in prescribing decisions. Furthermore, the broader label of rivaroxaban (approval for VTE primary prophylaxis following orthopedic surgery, DVT & PE treatment and secondary prophylaxis and in Europe has received a positive CHMP opinion for the prevention of secondary CV events in ACS) also carries significant weight in prescribing decisions among physicians.

Despite this, we feel that apixaban is well positioned to avoid the fate of ticagrelor. BMS and Pfizer are already increasing the level of marketing of apixaban which will increase physician awareness (a key point given that two-thirds of primary care physicians are still initiating warfarin therapy for SPAF). It also has a similar level of coverage in both the private space and Medicare compared to rivaroxaban in the United States. While ticagrelor was confronted with the generic entry of the well-established clopidogrel, apixaban and rivaroxaban are similarly priced. BMS and Pfizer are now also able to implement direct-to-consumer advertising for apixaban, which should increase patient awareness around the strength of its label in SPAF. Apixaban will likely soon be approved for DVT & PE treatment and secondary prophylaxis following the release of strong data from the AMPLIFY trial, and is pursuing a label for VTE primary prophylaxis following orthopedic surgery in the United States (it already has this label in the EU); it has a PDUFA date of March 15, 2014. With the expansion of indications in which apixaban will be approved and increased marketing, rivaroxaban's advantage in the SPAF market since launch may diminish. Indeed, apixaban may claim the market leading share that many forecast, just a little later than it should have.

Eamonn O'Connor is a business insights analyst with the Cardiovascular, Metabolic and Renal Disorders team at Decision Resources.

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