Landmark Study Shows that Adding Rivaroxaban to Standard Antiplatelet Therapy Significantly Reduced Secondary Cardiovascular Events in Patients with Acute Coronary Syndrome

ORLANDO, Fla., Nov. 13, 2011 /PRNewswire/ -- Johnson & Johnson Pharmaceutical Research & Development, L.L.C. announced today that adding oral rivaroxaban to standard antiplatelet therapy significantly reduced the composite primary efficacy endpoint of cardiovascular-related deaths, heart attacks or strokes in patients with acute coronary syndrome (ACS) compared to those receiving standard therapy alone. Results from the pivotal Phase 3 ATLAS ACS 2 TIMI 51 trial presented today at the American Heart Association Scientific Sessions and published in the New England Journal of Medicine also showed that rivaroxaban significantly increased rates of major bleeding, but did not create an excess risk of fatal bleeding over standard therapy alone.

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"The clinical benefit of giving rivaroxaban in combination with standard antiplatelet therapy seen in ATLAS TIMI 51 is welcome, and could lead to significant improvement in the management of patients with acute coronary syndrome," said Eugene Braunwald, M.D., Distinguished Hersey Professor of Medicine at Harvard Medical School and Founding Chairman of the Thrombolysis In Myocardial Infarction (TIMI) Study Group, Brigham and Women's Hospital.

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 directly cause a heart attack, or unstable angina, a condition signifying that a heart attack may soon occur. Each year, an estimated 1.2 million patients in the U.S. are discharged from the hospital with a primary or secondary diagnosis of ACS.

Results from the ATLAS ACS 2 TIMI 51 study showed that both 2.5 or 5 mg of rivaroxaban dosed twice daily (BID) in addition to standard therapy — low-dose aspirin with or without a thienopyridine such as clopidogrel — was superior to standard therapy alone in the primary efficacy endpoint of preventing secondary cardiovascular events (cardiovascular death, myocardial infarction or stroke) in patients with ACS [combined doses 8.9% vs. 10.7%(1) (P=0.008), Relative Risk Reduction (RRR) = 16%]. Additionally, rivaroxaban significantly reduced stent thrombosis compared with placebo [2.3% vs. 2.9% (P=0.02)].

Patients dosed with 2.5 mg BID of rivaroxaban showed a significant reduction in risk of the composite primary endpoint [9.1% vs. 10.7% (P=0.02)], driven by a significant 34% RRR in the rate of cardiovascular death [2.7% vs. 4.1% (P=0.002)]. There was also a significant reduction in deaths from any cause [2.9% vs. 4.5% (P=0.002)]. The 5 mg BID dose of rivaroxaban also significantly reduced the risk of the primary efficacy endpoint in the study [8.8% vs. 10.7% (P=0.03)].

The principal safety endpoint for the study was TIMI major bleeding events not associated with coronary artery bypass graft (CABG) surgery. In patients receiving rivaroxaban and standard therapy, rates were low overall, yet statistically significantly increased versus those treated with standard therapy plus a placebo [2.1% vs. 0.6% (P<0.001)]. Similarly, rivaroxaban exhibited higher rates of TIMI major bleeding events not associated with CABG surgery at both the 2.5 and 5 mg BID doses compared to placebo [1.8% vs. 0.6% (P<0.001) and 2.4% vs. 0.6% (P<0.001), respectively]. Importantly, these differences were not associated with an excess risk of fatal bleeding. Other treatment-emergent adverse events were generally balanced across treatment groups.

"For more than a decade ACS patients have been effectively treated with a low-dose aspirin given in combination with a thienopyridine to help reduce their risk of a recurrent cardiovascular event. This study showed that by adding the oral Factor Xa inhibitor rivaroxaban to standard therapy, this risk is greatly reduced, resulting in a significant reduction in mortality," said C. Michael Gibson, M.D., senior investigator of the TIMI Study Group, Harvard Medical School, and the Principal Investigator in the ATLAS ACS studies of rivaroxaban. "If the data from ATLAS ACS 2 TIMI 51 were extrapolated into clinical practice, we could potentially see one life saved for every 56 patients treated with this combination of therapies over a two year period."

The U.S. Food and Drug Administration (FDA) had previously granted rivaroxaban "fast track" designation for this indication. Fast Track designation allows the FDA to expedite review of drugs for serious or life-threatening conditions that demonstrate the potential to address unmet medical needs. Products in a fast track drug development program are eligible for priority review, but the FDA will only make their final determination upon review of the results.

"Results like these with a novel oral anticoagulant are unprecedented in acute coronary syndrome research," said Peter M. DiBattiste, M.D., Global Therapeutic Area Head, Cardiovascular and Metabolism, J&JPRD. "Adding rivaroxaban to standard therapy has the potential to significantly improve outcomes for patients, and we look forward to submitting these results to the FDA before the end of the year."

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 compared to placebo in preventing cardiovascular death, heart attack or stroke in ACS patients. Patients were given standard antiplatelet therapy – low-dose aspirin with or without a thienopyridine such as clopidogrel – plus rivaroxaban dosed at 2.5 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 and 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 and was funded and led by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. and Bayer HealthCare.

About Rivaroxaban

XARELTO® is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in people undergoing knee or hip replacement surgery, and for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. There are limited data on the relative effectiveness of XARELTO® and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well-controlled. XARELTO® belongs to a group of medicines called anticoagulants, and works by blocking the blood clotting Factor Xa, thereby reducing the tendency to form clots.

XARELTO® was the fifth New Drug Application approved by the U.S. FDA from the Janssen Pharmaceutical Companies in 2011.

Additionally, XARELTO® is being evaluated for the prevention and treatment of a broad range of disorders in which blood clotting plays a major role. The extensive program of clinical trials evaluating rivaroxaban makes the compound the most studied oral, Factor Xa inhibitor in the world today. By the time of its completion, more than 75,000 patients will have participated in the rivaroxaban clinical development program. Rivaroxaban is being developed jointly by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. and Bayer HealthCare.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD) is one of the Janssen Pharmaceutical Companies of Johnson & Johnson, the world's most broadly based producer of health care products. J&JPRD is headquartered in Raritan, N.J., and has facilities throughout Europe, the United States and Asia. J&JPRD is actively involved in drug discovery and development within a variety of therapeutic areas, including Cardiovascular and Metabolism, Central Nervous System, Immunology, Oncology and Virology, to address unmet medical needs worldwide. More information can be found at http://www.jnjpharmarnd.com.

Important Safety Information

WHAT IS THE MOST IMPORTANT INFORMATION I SHOULD KNOW ABOUT XARELTO®?

For people taking XARELTO® for atrial fibrillation:

People with atrial fibrillation (an irregular heart beat) are at an increased risk of forming a blood clot in the heart, which can travel to the brain, causing a stroke, or to other parts of the body. XARELTO® lowers your chance of having a stroke by helping to prevent clots from forming. If you stop taking XARELTO®, you may have an increased risk of forming a clot in your blood.

• Do not stop taking XARELTO® without talking to the doctor who prescribes it for you. Stopping XARELTO® increases your risk of having a stroke or forming blood clots in other parts of your body.

If you have to stop taking XARELTO®, your doctor may prescribe another blood thinner medicine to prevent a blood clot from forming.

• Take XARELTO® 1 time a day with your evening meal exactly as prescribed by your doctor.

For all people taking XARELTO®:

• XARELTO® can cause bleeding which can be serious, and rarely may lead to death. This is because XARELTO® is a blood thinner that reduces blood clotting.  While you take XARELTO® you are likely to bruise more easily and it may take longer for bleeding to stop.

You may have a higher risk of bleeding if you take XARELTO® and take other medicines that increase your risk of bleeding including:

• aspirin or aspirin containing products,
• non-steroidal anti-inflammatory drugs (NSAIDs)
• warfarin sodium (Coumadin®, Jantoven®)
• any medicine that contains heparin
• clopidogrel (Plavix®)
• prasugrel (Effient®)
• ticagrelor (Brilinta®)

Tell your doctor if you take any of these medicines. Ask your doctor or pharmacist if you are not sure if your medicine is one listed above.

Call your doctor or get medical help right away if you develop any of these signs or symptoms of bleeding:

• tingling, numbness or muscle weakness, especially in your legs.  This is particularly important if you had a procedure called spinal or epidural puncture as part of your anesthesia during surgery.
• any unexpected bleeding, or bleeding that lasts a long time (such as nose bleeds that happen often, unusual bleeding from gums, or menstrual bleeding that is heavier than normal or vaginal bleeding)
• bleeding that is severe or that you cannot control
• red, pink or brown urine
• bright red or black stools (look like tar)
• cough up blood or blood clots
• vomit blood or your vomit looks like "coffee grounds"
• headaches, feeling dizzy or weak
• pain, swelling, or new drainage at wound sites

WHO SHOULD NOT TAKE XARELTO®?

Do not take XARELTO® if you:

• currently have abnormal or unusual bleeding
• are allergic to rivaroxaban or any of the ingredients of XARELTO®  

WHAT SHOULD I TELL MY DOCTOR BEFORE OR WHILE TAKING XARELTO®?

Before taking XARELTO® tell your doctor if you:

• Have ever had bleeding problems
• Have liver or kidney problems
• Have any other medical condition
• Are pregnant or planning to become pregnant
• Are breastfeeding or plan to breastfeed

Tell all of your doctors and dentists that you are taking XARELTO®. They should talk to the doctor who prescribed XARELTO® for you before you have any surgery, medical or dental procedure.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some of your other medicines may affect the way XARELTO® works. Certain medicines may increase your risk of bleeding.

Especially tell your doctor if you take:

• ketoconazole (Nizoral®)
• itraconazole (Onmel™, Sporanox®)
• ritonavir (Norvir®)
• lopinavir/ritonavir (Kaletra®)
• indinavir (Crixivan®)
• carbamazepine (Carbatrol®, Equetro®, Tegretol®, Tegretol®-XR, Teril™, Epitol®)
• phenytoin (Dilantin-125®, Dilantin®, Phenobarbital, Solfoton™)
• phenobarbital (Solfoton™)
• rifampin (Rifater®, Rifamate®, Rimactane®, Rifadin®)
• St. John's wort (Hypericum perforatum)

Ask your doctor if you are not sure if your medicine is one listed above. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

HOW SHOULD I TAKE XARELTO®?

Take XARELTO® exactly as prescribed by your doctor. Do not change your dose or stop taking XARELTO® unless your doctor tells you to.

For people who have:

• atrial fibrillation: Take XARELTO® 1 time a day with your evening meal.  Stopping XARELTO® may increase your risk of having a stroke or forming blood clots in other parts of your body.
• hip or knee replacement surgery: Take XARELTO® 1 time a day with or without food.

• Your doctor may stop XARELTO® for a short time before any surgery, medical or dental procedure. Your doctor will tell you when to start taking XARELTO® again after your surgery or procedure.
• Do not run out of XARELTO®. Refill your prescription for XARELTO® before you run out.  When leaving the hospital following a hip or knee replacement, be sure that you will have XARELTO® available to avoid missing any doses.
• If you miss a dose of XARELTO®, take it as soon as you remember on the same day.
• If you take too much XARELTO®, go to the nearest hospital emergency room or call your doctor right away.

WHAT ARE THE POSSIBLE SIDE EFFECTS OF XARELTO®?

XARELTO® can cause bleeding which can be serious, and rarely may lead to death. Please see "What is the most important information I should know about XARELTO®?"

Tell your doctor if you have any side effect that bothers you or that does not go away.

Discuss any side effects with your doctor. You are also encouraged to report side effects to the FDA: visit http://www.fda.gov/medwatch or call 1-800-FDA-1088. You may also report side effects to Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (526-7736).

Please see full Product Information and Medication Guide.

Trademarks are those of their respective owners.

(This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Johnson & Johnson Pharmaceutical Research & Development, L.L.C. and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to, general industry conditions and competition; economic factors, such as interest rate and currency exchange rate fluctuations; technological advances and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; domestic and foreign health care reforms and governmental laws and regulations; trends toward health care cost containment; and increased scrutiny of the healthcare industry by government agencies. A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99 of Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended January 2, 2011. Copies of this Form 10-K, as well as subsequent filings, are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. Neither Johnson & Johnson Pharmaceutical Research & Development, L.L.C. nor Johnson & Johnson undertake to update any forward-looking statements as a result of new information or future events or developments.)

SOURCE Johnson & Johnson