Peripheral arterial disease (PAD) is a common form of the atherosclerotic disease. The pharmacological management of PAD encompasses the use of a wide array of drug classes, including antithrombotic agents, statins, anti-hypertensives, and vasoactive agents. The current European Society of Cardiology (ESC) guidelines recommend single or dual antiplatelet therapy with acetylsalicylic acid (ASA), and/or clopidogrel in symptomatic PAD patients. However, the approval of Xarelto on August 24, 2018, by the European Commission for the management of symptomatic PAD and coronary artery disease (CAD) patients who are at elevated risk of ischemic events, marks a new era for PAD management.
The basis of approval: Results from COMPASS trial
The European approval of Xarelto for PAD/CAD patients was based on the robust positive results from the Cardiovascular OutcoMes for People Using Anticoagulation StrategieS (COMPASS) trial (1,2). The trial is one of the largest studies in the PAD/CAD population and enrolled more than 27,000 patients. It was designed to evaluate three different treatment regimens-Xarelto 2.5 mg BID plus ASA, Xarelto 5 mg BID alone, and ASA 100 mg alone. Xarelto 2.5 mg BID plus ASA significantly reduced primary composite end point of cardiovascular death, stroke, or myocardial infarction (MACE) when compared with ASA alone. All-cause mortality was also lower for Xarelto 2.5 mg BID + ASA arm versus ASA alone. As expected, the major bleeding events reported for the rivaroxaban + ASA arm were higher versus ASA alone. For Xarelto alone, the rate of net clinical benefit was lower in comparison to ASA alone and was associated with elevated levels of major bleeding. The COMPASS trial was stopped approximately one year ahead of its scheduled completion due to noteworthy efficacy, and primary end point results.
DRG’s market outlook for Xarelto in Peripheral Arterial Disease
From a clinical standpoint, the combination of anticoagulant and antiplatelet therapy is an intriguing treatment approach to manage PAD patients. The rational being, thrombotic complications often play a key role in the poor prognosis of PAD patients. Given the complexity of the disease, not many agents have been successful in demonstrating positive clinical benefit in PAD patients. The combination of a vitamin K antagonist and an antiplatelet agent has not proven effective compared to antiplatelet therapy alone in PAD patients. Furthermore, in March 2018, Daiichi Sankyo’s ePAD study did not show significant benefit with edoxaban plus ASA versus clopidogrel plus ASA in PAD patients3. In October 2016, AstraZeneca’s Brilinta, an antiplatelet therapy, failed to meet its primary end point versus clopidogrel in the EUCLID study4. Brilinta was one of the front-running PAD emerging therapies, and its failure was a setback to the PAD market. These past failings cast doubt on the chances of success for Xarelto’s COMPASS trial. Consequently, the approval for Xarelto came as a surprise to the PAD domain. The combination of an antiplatelet agent and the low dose of Xarelto is thought to underlie the success of the COMPASS trial.
With no direct anticoagulant competition, we expect Xarelto to capture significant PAD market share. Additionally, we have high hopes for the ongoing Phase III VOYAGER-PAD study of Xarelto in symptomatic PAD patients undergoing peripheral revascularization. The VOYAGER-PAD trial is viewed as one of its kind among high-risk PAD patients, and the positive outcome from this study is expected to bolster the overall image, and performance, of Xarelto in the PAD market. The established position of Xarelto in the anticoagulant space will also contribute to the success of Xarelto in PAD.
With the failure of two pivotal studies in its life cycle management program, MARINER in medically ill patients, and COMMANDER-HF in heart failure patients, success in the PAD market is expected to play a key role in Bayer and Janssen’s expansion strategy for Xarelto. The anticipated U.S. FDA approval for PAD will further strengthen the overall position of Xarelto and help the drug maintain its throne in the anticoagulant space.
The entry of Xarelto in the PAD market, which is primarily genericized, has sparked enthusiasm in the management of PAD patients. We will be covering this exciting indication in an upcoming Disease Landscape & Forecast report to be published in December 2018.
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- Anand SS, et al. Major Adverse Limb Events and Mortality in Patients with Peripheral Artery Disease. JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY. 2018;71(20):2306-2315.
- Eikelboom JW, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. New England Journal of Medicine. 2017;377(14):1319-1330.
- Moll F, et al. Edoxaban Plus Aspirin vs Dual Antiplatelet Therapy in Endovascular Treatment of Patients with Peripheral Artery Disease: Results of the ePAD Trial. Journal of Endovascular Therapy. 2018;25(2):158-168.
- Hiatt WR, et al. Ticagrelor versus clopidogrel in symptomatic peripheral artery disease. New England Journal of Medicine. 2017;376(1):32-40.
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