title: The new oral anti-coagulants and the phase 3 clinical trials - a systematic review of the literature.
abstract: BACKGROUND
  Anticoagulation with vitamin K antagonists such as warfarin has historically been used for the long term management of patients with thromboembolic disease. However, these agents have a slow onset of action which requires bridging therapy with heparin and its analogues, which are available only in parenteral route. To overcome these limitations, new oral anticoagulants such as factor Xa inhibitors and direct thrombin inhibitors have been developed. The aim of this article is to systematically review the phase 3 clinical trials of new oral anticoagulants in common medical conditions.
  
  
  METHODS
  We searched PubMed (Medline) from January 2007 to February 2013 using "Oral anticoagulants", "New oral anticoagulants", "Randomized controlled trial", "Novel anticoagulants", "Apixaban", "Rivaroxaban", "Edoxaban", "Dabigatran etexilate", "Dabigatran" and a combination of the above terms. The available evidence from the phase 3 RCTs was summarized on the basis of individual drug and the medical conditions categorized into "atrial fibrillation", "acute coronary syndrome", "orthopedic surgery", "venous thromboembolism" and "medically ill patients".
  
  
  RESULTS
  Apixaban, rivaroxaban and dabigatran have been found to be either non-inferior or superior to enoxaparin in prophylaxis of venous thromboembolism in knee and hip replacement with similar bleeding risk, superior to warfarin for stroke prevention in atrial fibrillation with significant reduction in the risk of major bleeding, non-inferior to aspirin for reducing cardiovascular death and stroke in acute coronary syndrome with significant increase in the risk of major bleed. Rivaroxaban and dabigatran are also superior to the conventional agents in the management of symptomatic venous thromboembolism. However, compared to enoxaparin, apixaban and rivaroxaban use lead to significantly increased bleeding risk in medically ill patients. Additional studies evaluating the specific reversal agents of these new drugs for the management of life-threatening bleeding or other adverse effects are necessary.
  
  
  CONCLUSIONS
  Considering their pharmacological properties, their efficacy and bleeding complications, the new oral agents offer a net favourable clinical profile in orthopedic surgery, atrial fibrillation, acute coronary syndrome and increase the risk of bleeding in critically ill patients. Further studies are necessary to determine the long term safety and to identify the specific reversal agents of these new drugs.
authors.affiliation: Dow Medical College, Dow University of Health Sciences, Baba-e-Urdu Road, Karachi, Pakistan. faryal_tahir@hotmail.com.
authors.forename: Faryal
authors.initials: F
authors.lastname: Tahir
authors.forename: Haris
authors.initials: H
authors.lastname: Riaz
authors.forename: Talha
authors.initials: T
authors.lastname: Riaz
authors.forename: Maaz B
authors.initials: MB
authors.lastname: Badshah
authors.forename: Irbaz B
authors.initials: IB
authors.lastname: Riaz
authors.forename: Ameer
authors.initials: A
authors.lastname: Hamza
authors.forename: Hafsa
authors.initials: H
authors.lastname: Mohiuddin