Secondary Prevention of Acute Coronary Syndrome (ACS)
U.S. FDA Advisory Committee Recommends Against Approval of Bayer's Xarelto® (Rivaroxaban) to Reduce the Risk of Secondary Cardiovascular Events in Patients with ACS
May 23rd, 2012 - Berlin, Germany – Bayer HealthCare announced today that the U.S. Food and Drug Administration's (FDA's) Cardiovascular and Renal Drugs Advisory Committee voted against the approval of the oral anticoagulant Xarelto (rivaroxaban) 2.5 mg BID in combination with standard antiplatelet therapy to reduce the risk of secondary cardiovascular events in patients with Acute Coronary Syndrome (ACS).
"We appreciate the thoroughness of the Committee and, together with our cooperation partner Janssen Research & Development, LLC, we will ensure that the questions raised today are addressed so the FDA may finalize their review," said Dr. Kemal Malik, Member of the Bayer HealthCare Executive Committee and Head of Global Development.
Xarelto is approved in the U.S. to reduce the risk of blood clots in the legs and lungs of people who have just had knee or hip replacement surgery, and to reduce the risk of both hemorrhagic and thrombotic strokes as well as other blood clots in people with atrial fibrillation not caused by a heart valve problem.
Data presented at today's Advisory Committee meeting included results from the pivotal, global Phase III ATLAS ACS 2-TIMI 51 study, which compared oral rivaroxaban dosed twice daily in addition to standard antiplatelet therapy — low-dose aspirin with or without a thienopyridine such as clopidogrel — with standard antiplatelet therapy alone in preventing secondary cardiovascular events (cardiovascular death, myocardial infarction or stroke) in patients with ACS.
Results from the ATLAS ACS 2-TIMI 51 study, presented at the 2011 American Heart Association Scientific Sessions and published simultaneously in the New England Journal of Medicine (10.1056/NEJMoa1112277), showed that the combination of oral rivaroxaban 2.5 mg BID with standard antiplatelet therapy significantly reduced the composite primary efficacy endpoint of cardiovascular death, myocardial infarction or stroke in patients after a recent ACS compared to those receiving standard antiplatelet therapy alone. In addition, rivaroxaban 2.5 mg BID in combination with standard therapy significantly reduced the rate of cardiovascular mortality by 34% and the incidence of all-cause mortality by 32% over standard therapy alone, with the benefit established early and maintained through two years.
In patients receiving 2.5 mg BID of rivaroxaban in combination with standard antiplatelet therapy, the rate of TIMI major bleeding events not associated with coronary artery bypass graft (CABG) surgery were low overall, yet increased versus those treated with standard therapy alone. Importantly, these differences were not associated with an increase in the risk of fatal bleeding or fatal intracranial haemorrhage (ICH).
The FDA assigned a Priority Review designation to the supplemental New Drug Application (sNDA) filed by Bayer's cooperation partner Janssen Research & Development, LLC on December 29, 2011 for rivaroxaban in patients with ACS. Recommendations from the Advisory Committee will be considered by the FDA in its review of the sNDA for rivaroxaban in this indication, but the FDA is not bound to follow them. If approved by the FDA, Janssen Pharmaceuticals, Inc. (a Johnson & Johnson Company) will commercialize rivaroxaban for this additional indication in the U.S.
ACS is a complication of coronary heart disease, which is the leading cause of death in the U.S. and one of the most prevalent non-communicable diseases in the world. ACS occurs when a blood clot blocks a coronary artery, reducing blood supply to the heart. This disruption of blood flow can be the direct cause of a myocardial infarction, or cause unstable angina indicating that a myocardial infarction may soon occur.
About ATLAS ACS 2-TIMI 51
The ATLAS ACS 2-TIMI 51 (Anti-Xa Therapy to Lower cardiovascular events in Addition to aspirin with/without thienopyridine therapy in Subjects with Acute Coronary Syndrome) study was designed to test the efficacy of rivaroxaban, in combination with standard antiplatelet therapy, compared to placebo in preventing cardiovascular death, myocardial infarction or stroke in patients with ACS. Patients were given standard antiplatelet therapy plus rivaroxaban dosed at 2.5 mg or 5 mg BID, or a placebo. Of the 15,526 patients randomized into the study, 93% received aspirin and thienopyridine in addition to rivaroxaban or placebo, and the balance were treated with aspirin plus rivaroxaban or placebo.
The double blind, randomized, placebo-controlled study was coordinated by the TIMI Study Group and Brigham and Women's Hospital and Harvard Medical School, Boston, U.S., and was funded and led by Bayer HealthCare and Janssen Research & Development, LLC.
About Venous Arterial Thromboembolism (VAT)
Thrombosis is the formation of a blood clot inside a blood vessel, blocking a vein (venous thrombosis) or artery (arterial thrombosis). Venous Arterial Thromboembolism (VAT) is caused when some or all of a clot detaches and is moved within the blood stream until it obstructs a smaller vessel. This can result in damage to vital organs, because the tissue beyond the blockage no longer receives nutrients and oxygen.
VAT is responsible for a number of serious and life threatening conditions:
- Venous Thromboembolism (VTE) occurs when part of a clot formed in a deep vein, for example in the leg (known as deep vein thrombosis, or DVT), is carried to the lung, via the heart, preventing the uptake of oxygen. This is known as a pulmonary embolism (PE), an event which can be rapidly fatal
- Arterial Thromboembolism (ATE) occurs when oxygenated blood flow from the heart to another part of the body (via an artery) is interrupted by a blood clot. If this occurs in a vessel supplying blood to the brain, it can lead to a stroke, an event that can be severely debilitating or fatal. If it occurs in a coronary artery, it can lead to acute coronary syndrome (ACS), a complication of coronary heart disease which includes conditions such as myocardial infarction (heart attack), and unstable angina
VAT is responsible for significant morbidity and mortality, and requires active or preventative treatment to avoid potentially serious or fatal patient outcomes.
About Rivaroxaban (Xarelto)
Rivaroxaban is an oral anticoagulant that was discovered in Bayer HealthCare's Wuppertal laboratories in Germany, and is being jointly developed by Bayer HealthCare and Janssen Research & Development, LLC. It has a rapid onset of action with a predictable dose response and high bioavailability, no requirement for routine coagulation monitoring, and a limited potential for food and drug interactions.
Rivaroxaban is marketed under the brand name Xarelto for VTE prevention in adult patients following elective hip or knee replacement surgery, and it is the only oral anticoagulant that has consistently demonstrated superior efficacy over enoxaparin in this indication. Rivaroxaban is approved in more than 120 countries worldwide and is marketed outside the U.S. by Bayer HealthCare in this indication. On December 9, 2011, Xarelto received further marketing approval in the EU for the prevention of stroke and systemic embolism in patients with atrial fibrillation, as well as for the treatment of deep vein thrombosis (DVT) and the prevention of recurrent DVT and pulmonary embolism following an acute DVT in adult patients.
In the U.S., where rivaroxaban has been available since July 2011 for VTE prevention in adult patients following elective hip or knee replacement surgery, Janssen Pharmaceuticals, Inc. (a Johnson & Johnson Company) holds marketing rights. The Bayer HealthCare sales force is supporting Janssen Pharmaceuticals, Inc. in designated hospital accounts. On November 4, 2011, Xarelto received further marketing approval in the U.S. to reduce the risk of stroke and systemic embolism in patients with nonvalvular Atrial Fibrillation.
The extensive clinical trial program supporting rivaroxaban makes it the most studied and widely published oral, direct Factor Xa inhibitor. The studies involve over 75,000 patients for the prevention and treatment of venous and arterial thromboembolic (VAT) disorders across a broad range of acute and chronic conditions, including VTE prevention in adult patients following elective hip or knee replacement surgery, stroke prevention in patients with Atrial Fibrillation, VTE treatment and the prevention of recurrent DVT or PE, and for secondary prevention after an Acute Coronary Syndrome.
To learn more about thrombosis, please visit www.thrombosisadviser.com.
About Bayer HealthCare
The Bayer Group is a global enterprise with core competencies in the fields of health care, nutrition and high-tech materials. Bayer HealthCare, a subgroup of Bayer AG with annual sales of EUR 17.2 billion (2011), is one of the world's leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Consumer Care, Medical Care and Pharmaceuticals divisions. Bayer HealthCare's aim is to discover, develop, manufacture and market products that will improve human and animal health worldwide. Bayer HealthCare has a global workforce of 55,700 employees (Dec 31, 2011) and is represented in more than 100 countries. Find more information at www.bayerhealthcare.com.
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- Acute coronary syndrome
- An umbrella term used to cover any group of clinical symptoms compatible with an acute heart attack. The subtypes of acute coronary syndrome include unstable angina (in which the heart muscle is not damaged), and two forms of heart attack in which the heart muscle is damaged. These latter types are named according to the appearance of the electrocardiogram as non-ST segment elevation myocardial infarction (NSTEMI) and ST segment elevation myocardial infarction (STEMI).
- Atrial fibrillation
- A heart rhythm disorder where chambers in the upper heart (atria) beat more rapidly than those in the lower section of the heart. Blood is not pumped out of the upper chambers completely during beating, and may pool and form a clot. A stroke results if a section of clot dislodges from the upper chambers and becomes lodged in the brain.
- The ability of a drug to produce the desired effect.
- Formation of a clot inside a blood vessel.
- Venous thromboembolism
- A disease process beginning with a blood clot occurring within the venous system, including deep vein thrombosis and pulmonary embolism.
- Factor Xa
- Pivotal component of blood clotting cascade. Stimulates the production of thrombin, the enzyme in the coagulation cascade that promotes the formation of blood clots.
- Deep vein thrombosis
- A blood clot in a deep vein, usually resulting from damage to the vein or blood flow slowing down or stopping. Usually DVTs are found in the leg, but can also be in the arm. Distal DVTs are found in deep veins of the calf, and are the most common type of DVT. Proximal DVTs are found in the legs above the calf muscle up to the waist.
- Pulmonary embolism
- A potentially fatal condition caused by a blood clot blocking a vessel in the lung: usually the clot originates from a DVT in the legs. PE can result in permanent lung damage.