Thin on the ground

Venous thromboembolism (VTE), a term that refers to a situation in which a patient has both a pulmonary embolism (PE) and deep vein thrombosis (DVT), is one of the most common life-threatening cardiovascular conditions.

In the EU, nearly half a million patients die from VTE each year. In the US, over two million patients suffer from the condition, with over half developing VTE either in hospital or in the 30 days post-hospitalisation. Patients at a particularly high risk for developing VTE are those undergoing major orthopaedic surgery, including total hip replacement (THR) and total knee replacement (TKR). This common condition also has a significant economic impact: incremental in-patient costs are estimated at $10,000 per DVT and $20,000 per PE.

The standard method of VTE prevention for the past 20 years has been routine thromboprophylaxis with anticoagulant agents. The anticoagulant therapies recommended to prevent VTE after orthopaedic surgery include low molecular weight heparin (such as enoxaparin sodium), vitamin K antagonists (including warfarin) and fondaparinux sodium. Although these drugs have proven efficacy, each category lacks many properties of the 'ideal' anticoagulant. Heparins and fondaparinux, for example, require parenteral administration and warfarin, although able to be administered orally, has a narrow therapeutic window and a slow onset of action, along with unpredictable pharmacology. Additionally, many foods and drugs interact with warfarin. As a result, patients are required to undergo routine coagulation monitoring, which is time-consuming, costly and detrimental to quality of life.

Recently approved
Bayer and Johnson & Johnson's rivaroxaban (Xarelto) is an oxazolidinone-based, active site-directed, factor Xa inhibitor. Rivaroxaban has a high bioavailability, a predictable pharmacological profile and a rapid onset of action, and neither routine coagulation monitoring nor dose adjustment is required. Health Canada and the European Commission have already granted rivaroxaban marketing authorisation for thromboprophylaxis in hip/knee surgery patients. The authorisation was based on data from the RECORD 1 and 2 (THR patients) and RECORD 3 and 4 (TKR patients) studies, which showed that rivaroxaban has non-inferior and possibly superior efficacy compared with enoxaparin (40mg/day).

Another oral anticoagulant approved for thromboprophylaxis in orthopaedic patients in the EU, Canada and other countries is the direct thrombin inhibitor dabigatran etexilate, which Boehringer Ingelheim markets under the names Pradax, Pradaxa and Pradaxar. By specifically blocking the activity of thrombin (both free and clot-bound), direct thrombin inhibitors are able to achieve potent antithrombotic effects. Dabigatran is not metabolised by the CYP enzyme system, making related drug interactions unlikely; it has predictable anticoagulation and does not require routine coagulation monitoring or dose adjustment. Additionally, it is backed by positive study data. The RE-NOVATE II trial showed that, in terms of preventing VTE after THR surgery, dabigatran 220mg/day is as effective and safe as the European enoxaparin 40mg/day regimen. The RE-MODEL trial showed similar results in patients undergoing TKR surgery. However, the RE-MOBILIZE study found dabigatran to be inferior to the North American postoperative enoxaparin 60mg/day regime. 

These two new oral anticoagulants, rivaroxaban and dabigatran, were incorporated into the 2009 NICE guidelines "Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital". The guidelines recommend starting dabigatran 1–4 hours after surgery and rivaroxaban 6–10 hours after surgery. Therapy should be continued for 28–35 days in THR patients and 10–14 days in TKR patients. According to inThought analysts, the odds of rivaroxaban and dabigatran being approved in the US for this indication are 95 per cent and 82 per cent, respectively. 

Recently launched products 

­What else is in the pipeline?
In April 2007, Bristol-Myers Squibb and Pfizer entered into a worldwide agreement to develop and commercialise an oral pyrazole-based factor Xa inhibitor, apixaban, for a broad range of thrombotic conditions. Apixaban has fixed daily dosing and low potential for drug interactions. In the first phase III trial (ADVANCE-1), compared with the US regimen of enoxaparin, apixaban failed to show a benefit in terms of preventing VTE, but was associated with significantly less bleeding. The second trial (ADVANCE-2) used the European regimen of enoxaparin as a comparator and demonstrated that apixaban was statistically superior in reducing the incidence of VTE, without an increase in the risk of bleeding in patients undergoing TKR surgery. A third trial, ADVANCE-3, which examined patients undergoing THR surgery, was completed in September 2009, but results were not available at the time of going to press.

Daichii Sankyo is developing edoxaban tosylate, which is also an orally active direct factor Xa inhibitor. In April 2010 the company submitted an NDA in Japan for edoxaban in the prevention of VTE after major orthopaedic surgery. The submission was supported by data from two pivotal phase III studies, which showed once-daily oral administration of edoxaban reduced the incidence of VTE in patients undergoing TKR or THR, and confirmed non-inferiority to enoxaparin.

YM 150 is an oral anticoagulant that directly and specifically inhibits factor Xa, which is in development by Astellas Pharma in Japan and other Asian countries. Data from the phase II ONYX-2 trial showed doses of YM 150 ranging from 30mg to 120mg had comparable efficacy to enoxaparin without an increase in major bleeding events. The phase III ONYX-3 trial, which completed enrolment in April 2010, plans to compare once- and twice-daily doses of YM 150 and enoxaparin in patients undergoing elective hip replacement surgery. According to inThought, based on analyses of clinical data, trial design and historical approval rates of similar drugs, the likelihood of YM 150 gaining approval is average (22 per cent).

Where do we go from here?
The 'ideal' prophylactic drug would reduce the frequency of VTE without causing bleeding and other complications in patients postoperatively. This ideal drug would be able to be administered orally once daily; it would have predictable dose response and kinetics, a wide therapeutic window, and would not require routine coagulation monitoring. It would also have little interaction with other drugs or food, have non-specific plasma protein binding, and be able to inhibit both free and clot-bound coagulation factors.

Regardless of which of these drugs gains approval, patients and physicians will still benefit from new therapeutic options bringing them closer to the ideal anticoagulant.

The Author
Pipeline was written by Celeste Burness of of Adis International - Wolters Kluwer Pharma Solutions - using data derived from Adis R&D Insight, Clinical Trials Insight and inThought 
For information on Adis services, contact Kuljeet Sohanpal on 0207 981 0714 or email: Kuljeet.Sohanpal@wolterskluwer.com

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