Pradaxa – Oral Direct Thrombin Inhibitor

Pradaxa (dabigatran etexilate) is a new oral anticoagulant under development by Boehringer Ingelheim. Its primary indication is for prevention of venous thromboembolism (VTE) following orthopaedic surgery, such as operations for total hip and total knee replacement.

Within a year of filing for regulatory approval with the EMEA in early 2007, the company received positive news that the Committee for Medicinal Products in Human Use (CHMP) had recommended Pradaxa's approval for thromboprophylaxis. Subsequent authorisation to market Pradaxa followed and it is now in the process of being launched in countries throughout Europe.

THE BURDEN OF VTE

VTE is the formation of a blood clot or thrombus in the vein, which may occlude the vein or rupture and lodge elsewhere in the body, such as an artery. VTE encompasses both deep-vein thrombosis (DVT) and pulmonary embolism (PE), in which clots formed in the deep veins of the leg rupture and become lodged in the pulmonary artery. After heart attack and stroke, it is the third most common cardiovascular disease.

In the US alone, it is estimated that 2 million people are affected by VTE. Of these 60,000 die from PE, which occurs when a clot in the deep veins of the leg breaks away and becomes lodged in the pulmonary artery.

In the majority of cases VTE is a silent disease, producing no overt symptoms and as a consequence probably under-diagnosed.

Patients undergoing major orthopaedic surgery (hip or knee replacements and hip fracture) are at an especially high risk of developing VTE. Without anticoagulant therapy, between 40% and 50% of patients undergoing hip replacement surgery suffer VTE. This rises to 70–80% in hip fracture surgery.

ALTERNATIVES TO WARFARIN NEEDED

In clinical use for some 50 years, the vitamin K antagonist warfarin remains the standard long-term oral anticoagulant. Although effective when well managed, it has a number of significant drawbacks that can have potential thrombotic and haemorrhagic consequences.

Thromboprophylaxis with warfarin is influenced by genetic differences in metabolism, concurrent medication use, vitamin K intake, drug interactions, and alcohol consumption among others. Thus, to keep patients within the International Normalised Ratio (INR) target range, daily maintenance doses of warfarin can vary from less than 1 to over 20mg/day. This necessitates regular coagulation monitoring and dosage adjustments.

Warfarin is an indirect thrombin inhibitor and depletes vitamin K-dependent clotting factors, particularly prothrombin, when exerting its antithrombotic effect. Pharmacologically this results in a slow onset of action. Thus, when rapid anticoagulation is indicated, patients have to take overlapping parenteral antithrombin therapy with heparins. Finally, warfarin has a long half-life, which together with the half-life of the vitamin K-dependent clotting factors slows its offset of action.

The drawbacks associated with warfarin have spurred the search for alternative orally administered drugs that more closely meet the ideal criteria for anticoagulant therapy. These include:

• Once or twice-daily oral administration
• High therapeutic index with standardised dosages
• Rapid onset and offset of action
• No requirement for routine coagulation monitoring
• Minimal interaction with food or drugs

Studies on Pradaxa indicate that this new oral anticoagulant has a rapid onset and offset of action and predictable anticoagulation action, removing the need for coagulation monitoring. There is also no evidence to suggest it interacts with food, while its potential to interact with other drugs is considered low.

PRADAXA IN VTE PREVENTION

Clinical data from the RE-NOVATETM and RE-MODELTM trials, included in regulatory submissions to the EMEA, support the clinical efficacy of Pradaxa in VTE prevention. At doses of 150 or 220 mg, orally administered Pradaxa proved as safe and effective as the injectable LMW heparin, enoxaparin 40mg, in preventing VTE and all cause mortality following total hip and knee replacement surgery.

Incidence of major bleeding, the main safety concern with thromboprophylaxis, was comparable between treatment arms and low in both trials (range 1.3–2.0%). Likewise, the incidence of raised hepatic enzyme levels was similar between treatment arms.

Pradaxa's first indication is for VTE prevention. The company is also exploring the drug’s potential in stroke prevention in patients with atrial fibrillation (AF), where Pradaxa is being evaluated in the 18,000-patient RE-LY trial.

MARKETING COMMENTARY

Developing a suitable alternative to warfarin has been the driving force of anticoagulant research for years. Hopes were first raised at the end of 2003 when Exanta (ximelagatran), an oral direct thrombin inhibitor, was approved in Europe. However, they were subsequently dashed when it was withdrawn from the market in 2006 because of hepatic toxicity.

Hopes have now been raised again with EMEA approval of Pradaxa. Also waiting in wings are two other oral anticoagulants that are likely to challenge Pradaxa in the market for thromboprophylaxis, Bayer's Xarelto (rivaroxaban) and BMS/Pfizer's apixaban.