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Results of COMMANDER HF and MARINER studies with rivaroxaban published


Studies in very sick patient populations reaffirm and further strengthen the safety profile of rivaroxaban / Study results did not show a statistical difference in primary endpoints / COMMANDER HF study evaluated rivaroxaban in patients following an acute decompensation of heart failure and concomitant coronary artery disease / MARINER study evaluated rivaroxaban in acutely medically ill patients

New data presented at ESC Congress 2018:

Berlin, August 27, 2018 - Bayer AG and its development partner Janssen Research & Development, LLC today announced new data from two investigational studies for its Factor Xa inhibitor rivaroxaban (Xarelto®) at ESC Congress 2018, 25-29 August in Munich, Germany.

"Sudden worsening of the symptoms of heart failure is serious and often requires hospitalization to manage worsening breathlessness and swelling of the legs," said Professor John Cleland, Professor of Cardiology at Imperial College London, UK. "While the COMMANDER HF study demonstrated that rivaroxaban offers no additional benefit on top of standard of care in this group of patients, rivaroxaban did numerically reduce both heart attacks and stroke, suggesting that it did have a beneficial effect on thrombosis. The composite efficacy result was driven primarily by all-cause mortality which was mostly due to worsening of the heart’s pumping function; these deaths represented about one third of all deaths in this very sick patient population. Rivaroxaban may reduce the risk of heart attack and stroke but these do not appear to be key drivers of prognosis in the long term setting after an episode of decompensated heart failure in contrast to the large number of patients with milder and more stable heart failure."

Data from the COMMANDER HF study showed that, in patients following an acute decompensation of heart failure and concomitant coronary artery disease, there was no statistically significant difference between rivaroxaban 2.5 mg twice daily and placebo, each on top of standard of care, in reducing the composite risk of all-cause mortality, heart attack and stroke. However, there were numerically fewer events for both heart attack and stroke in patients receiving rivaroxaban. Furthermore patients receiving rivaroxaban had similar and in general low rates of severe bleeding compared to those receiving placebo.

Separately, data from the MARINER study showed that, compared to placebo, rivaroxaban 10 mg once daily (1) did not significantly reduce the composite of symptomatic venous thromboembolism (VTE) and VTE-related death post hospital discharge in high-risk acutely medically ill patients. The major bleeding rate with rivaroxaban was generally low, and not significantly different compared to placebo.

The positive benefit risk profile of rivaroxaban in the approved indications remains unchanged.

"The data presented at ESC Congress 2018 provide additional information on the management of patients at risk of cardiovascular events and we are committed to continuing to investigate rivaroxaban in these special patient populations who currently have limited treatment options," said Dr Joerg Moeller, Member of the Executive Committee at Bayer AG’s Pharmaceuticals Division and Head of Research and Development. "Rivaroxaban has the most extensive clinical study programme of any non-vitamin K antagonist oral anticoagulant (NOAC) and we continue to research which patients may benefit most from rivaroxaban."

About the COMMANDER HF Study
COMMANDER HF is a Phase III international prospective, randomized, double-blind, placebo controlled, event-driven, parallel-group comparison, designed to evaluate the use of rivaroxaban in reducing the risk of morbidity and mortality in patients following an acute decompensation of heart failure and concomitant coronary artery disease.

The study evaluated 5,025 patients from 32 countries worldwide following an acute decompensation of heart failure and significant coronary artery disease (CAD) who were already receiving appropriate treatment for their heart failure and CAD.

Patients were randomized in a 1:1 ratio to receive either rivaroxaban 2.5 mg twice daily or placebo, both in combination with standard of care for heart failure and CAD (as prescribed by the patient’s physician).

For the primary efficacy outcome of the composite of all-cause mortality (ACM), heart attack and stroke, patients treated with rivaroxaban had an event rate of 13.44 (per 100 patients per year), compared to 14.27 in patients treated with placebo, with no statistical difference between the patient populations (hazard ratio (HR) 0.94; 95% confidence interval (CI) 0.84-1.05). Specifically, there were numerical reductions in the individual outcomes of heart attack and stroke in patients treated with rivaroxaban compared to placebo - relative risk reduction 17% (HR 0.83; 95% CI 0.63-1.08) and 34% (HR 0.66; 95% CI 0.47-0.95) respectively - however these were not statistically significant.

For the primary safety outcome of fatal bleeding or bleeding into a critical space with potential for permanent disability, rates for rivaroxaban were comparable to placebo (HR 0.80; 95% CI 0.43-1.49).

About the MARINER Study
MARINER is a Phase III randomized, double-blind, placebo-controlled trial, designed to evaluate the efficacy and safety of venous thromboembolism (VTE) prophylaxis in high-risk acutely medically ill patients using rivaroxaban, begun at hospital discharge and continued for 45 days.

The study evaluated 12,024 patients aged ≥ 40 years from 36 countries worldwide who were hospitalized for 3-10 days prior to randomization for heart failure, acute respiratory insufficiency or acute exacerbation of chronic obstructive pulmonary disease (COPD), acute ischemic stroke, acute infectious diseases, or inflammatory diseases including rheumatic disease and were at an increased risk for VTE.

Patients were randomized in a 1:1 ratio to receive either rivaroxaban 10 mg once daily (CrCl ≥ 50ml/min) or placebo for 45 days post hospital discharge; patients randomized to rivaroxaban with CrCl 30-<50ml/min received rivaroxaban 7.5 mg once daily.

The primary efficacy outcome of symptomatic VTE and VTE-related death occurred at a rate of 0.83% in patients treated with rivaroxaban compared to 1.10% in patients receiving placebo, a 24% relative risk reduction (HR 0.76, 95% CI 0.52-1.09). However this result was not statistically significant.

There was a nominally significant 56% reduction in symptomatic VTE in patients treated with rivaroxaban compared to those treated with placebo, with an absolute difference of 0.24% (HR 0.44; 95% CI 0.22-0.89). VTE related death rates were lower in rivaroxaban group but not significantly different compared to placebo.

Rates of major bleeding, the primary safety outcome, were generally low across both treatment groups, and not significantly different (0.28% vs 0.15%, HR 1.88, 95% CI 0.84-4.23).

About Rivaroxaban (Xarelto®)
Rivaroxaban is the most broadly indicated non-vitamin K antagonist oral anticoagulant (NOAC) worldwide and is marketed under the brand name Xarelto®. Xarelto is approved for more venous and arterial thromboembolic (VAT) conditions than any other NOAC:

• The prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (AF) and one or more risk factors

• The treatment of pulmonary embolism (PE) in adults

• The treatment of deep vein thrombosis (DVT) in adults

• The prevention of recurrent PE and DVT in adults

• The prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip replacement surgery

• The prevention of VTE in adult patients undergoing elective knee replacement surgery

• The prevention of atherothrombotic events after an Acute Coronary Syndrome in adult patients with elevated cardiac biomarkers when co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine

• The prevention of atherothrombotic events in adult patients with coronary artery disease (CAD) or symptomatic peripheral artery disease (PAD) at high risk for ischaemic events when co-administered with acetylsalicylic acid (ASA)

Whilst licences may differ from country to country, across all indications Xarelto is approved in more than 130 countries.

Rivaroxaban was discovered by Bayer, and is being jointly developed with Janssen Research & Development, LLC. Xarelto is marketed outside the U.S. by Bayer and in the U.S. by Janssen Pharmaceuticals, Inc. (Janssen Research & Development, LLC and Janssen Pharmaceuticals, Inc. are part of the Janssen Pharmaceutical Companies of Johnson & Johnson).

Anticoagulant medicines are potent therapies used to prevent or treat serious illnesses and potentially life-threatening conditions. Before initiating and while continuing treatment with anticoagulant medicines, physicians should carefully assess the benefit and risk for the individual patient.

Responsible use of Xarelto is a very high priority for Bayer, and the company has developed a Prescribers Guide for physicians and a Xarelto Patient Card for patients to support best practice.

To learn more about thrombosis, please visit www.thrombosisadviser.com and www.vascularadviser.com
To learn more about Xarelto, please visit www.xarelto.com

(1)Patients with CrCl ≥ 50ml/min were treated with rivaroxaban 10 mg once daily, whilst rivaroxaban 7.5 mg once daily was given in patients with CrCl 30-<50ml/min

About Bayer
Bayer is a global enterprise with core competencies in the Life Science fields of health care and agriculture. Its products and services are designed to benefit people and improve their quality of life. At the same time, the Group aims to create value through innovation, growth and high earning power. Bayer is committed to the principles of sustainable development and to its social and ethical responsibilities as a corporate citizen. In fiscal 2017, the Group employed around 99,800 people and had sales of EUR 35.0 billion. Capital expenditures amounted to EUR 2.4 billion, R&D expenses to EUR 4.5 billion. For more information, go to www.bayer.com.

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Forward-Looking Statements
This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer’s public reports which are available on the Bayer website at www.bayer.com. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.



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