2012 Annual Report Cardiovascular Disease In late 2012, Bristol-Myers Squibb  received regulatory approvals for  Eliquis  (apixaban) in the U.S., EU,  Japan and Canada. Tested in one of  the largest clinical trial programs ever  undertaken, it was approved to reduce  the risk of stroke and systemic embo- lism in patients with nonvalvular atrial  fibrillation, the most common cardiac  arrhythmia. Without lifelong treat- ments, these patients are at serious  risk of developing strokes.  Clinical studies comparing  Eliquis (a Factor Xa inhibitor) to warfarin, the  standard of care for almost 60 years,  found that  Eliquis  was superior in  reducing stroke and systemic embo- lism, major bleeding and mortality. In  a trial comparing  Eliquis  to aspirin in  patients who could not take warfarin,  Eliquis  showed a substantial reduc- tion in stroke risk, without a significant  increase in major bleeding compared  to aspirin. “While it took more than a decade to  bring  Eliquis  to patients, it remains the only drug in its class that shows  superiority against warfarin in patients  with atrial fibrillation in all three mea- sures: stroke and systemic embolism,  major bleeding and mortality,” says  Jack Lawrence, M.D.,  Eliquis  full devel- opment lead. Scientists at DuPont  Pharmaceuticals, which we acquired  in 2001, provided the first clinical  proof that direct Factor Xa inhibition  with a small molecule was an effective  approach to preventing clots. In addition to recent approvals for  stroke risk reduction in atrial fibrillation,  in 2011  Eliquis  received clearance in  the EU to prevent venous thromboem- bolic events (VTEs) following elective  New approaches are in earlier devel- hip and knee replacement surgeries.  Beyond VTE prevention in the ortho- pedic setting, the company is studying  Eliquis  for VTE treatment, with the first  of two large studies finding that  Eliquis was superior to placebo in preventing  recurrent VTEs in patients who had  completed a standard anticoagula- tion course of therapy. Treatment with  Eliquis  for an additional year reduced  the risk of the combined endpoint of  recurrent VTEs and total mortality.  Although patients on  Eliquis  are at risk  for bleeding, in this study  Eliquis  did not  show an increase in major bleeding. A  second trial is studying whether  Eliquis can replace the current standard of  care as an initial course of treatment.  opment. For example, along with Pfizer,  our development and commercializa- tion partner for  Eliquis , Bristol-Myers  Squibb is collaborating with Portola  Pharmaceuticals to develop a novel  reversal agent for urgent clinical situa- tions where reversing the anticoagula- tion effects of certain blood thinners,  including  Eliquis , is needed.  Other R&D efforts are focused on  heart failure, for which there are  few new effective treatments, with  a long-acting version of relaxin, a  naturally occurring peptide that has the  potential to improve cardiac function  and patient survival. Also being studied  is a next-generation anticoagulant to  treat strokes as well as a compound  that may be able to normalize the  rhythms of atrial fibrillation. Therapeutic  approaches for atherosclerosis include  a novel therapy to remove cholesterol  from plaque and a robust approach to  lowering LDL (bad) cholesterol that,  when combined with statins, poten- tially would allow patients to achieve  their cholesterol-lowering goals. ease remains the leading cause of  death worldwide. That’s why we are  developing both our cardiovascular  and metabolic disease portfolios to  focus on cardiovascular event reduc- tion. Several of our novel diabetes  agents –  Byetta  (exenatide),  Bydureon  (exenatide extended-release for  injectable suspension) and  Forxiga (dapagliflozin) – have demonstrated  reductions in weight and blood pres- sure, two major risk factors for heart  disease, while helping to control  glucose levels, a third major risk factor.  Onglyza  (saxagliptin),  Bydureon  and  Forxiga  are being studied for their  potential to be cardio-protective (also see pages 16-17). Lawrence believes the attributes that  helped bring  Eliquis  to market will also  aid in developing a robust cardiovascu- lar pipeline. “Our success with  Eliquis speaks to the successful efforts of our  global clinical development program  that tested  Eliquis  at 4,000 sites,  exploring five potential indications con- currently in nine large Phase III studies  involving more than 60,000 patients,”  he says. “And it speaks to the talent  and dedication of biologists, chemists  and clinicians, who were involved in this  pioneering Factor Xa program starting  in 1994 and those who have stayed  with this effort to this day.” r 12 Bristol-Myers Squibb  Eliquis  joins other company efforts  to reduce potentially debilitating and  sometimes deadly cardiovascular  events. After all, even with multiple  interventions available, heart dis-