New oral anticoagulants - clinical applications

Rivaroxaban and dabigatran etexilate are oral anticoagulants that promise to be as effective as warfarin, but easier to use. The new drugs have shown similar or greater efficacy than low molecular weight heparins and comparable safety in the prevention of venous thromboembolism after hip or knee arthroplasty. Unlike other anticoagulants, routine monitoring is not required during short-term use. The drugs are also being assessed for other indications that include treatment of venous thromboembolism and preventing stroke in atrial fibrillation. Only the results of ongoing studies will tell if they can match warfarin and the heparins across their full range of clinical indications.

The two widely used classes of anticoagulant are the heparins, and the vitamin K antagonists such as warfarin. Heparins are best suited for short-term prevention and initial treatment of venous thromboembolism or arterial occlusion, but can be given long-term. Warfarin is the mainstay of long-term therapy and is also used for atrial fibrillation and patients with mechanical heart valves. These drugs are highly effective, but have well-known limitations in addition to the risk of bleeding. Heparins require injection or infusion. Warfarin has a narrow therapeutic window, variable dose response and multiple interactions with other drugs and concurrent illnesses, and there is a need for frequent laboratory monitoring of dose– effect.

Rivaroxaban and dabigatran etexilate are new oral anticoagulants which should be simpler to use than heparins or warfarin^.1,2They have predictable oral bioavailability and pharmacokinetics, few drug interactions and are suitable for daily dosing.^3,4One dose regimen should suit most patients regardless of body weight, age and gender without the need for laboratory monitoring.

As the Australian population ages there will be increasing demand for elective hip or knee replacement and surgery after hip fracture. As these procedures are often complicated by thromboembolism, clinical practice guidelines recommend effective anticoagulant prophylaxis for at least ten days after surgery.⁵Enoxaparin is the most widely used low molecular weight heparin. In Australia and Europe 40 mg is given daily, whereas in North America the dose is 30 mg 12-hourly. Despite prophylaxis, about 2.5% of patients develop symptomatic deep vein thrombosis or pulmonary embolism during the three months after major joint surgery. About two-thirds of cases occur after discharge from hospital.^6,7In clinical trials subclinical deep vein thrombosis is found despite effective prophylaxis in up to 30% of patients when screening venography is done 7–10 days after surgery. The rate of clinical thromboembolism after hip replacement is reduced when prophylaxis is continued for 4–5 weeks after discharge. Selected patients who have an ongoing risk of thromboembolism after knee replacement may also benefit from extended prophylaxis.⁵

Surgeons are wary of surgical bleeding after joint replacement since wound haematoma delays recovery and may predispose to infections that can endanger the prosthesis. This adds importance to evidence regarding the balance of efficacy and risk of bleeding with the new anticoagulants.

In clinical trials the efficacy of the new drugs was assessed by the incidence of total, major and clinical venous thromboembolism (see below). The primary measure of efficacy was the incidence of 'total venous thromboembolism'. A reduction in this composite end point has been accepted by government regulators and most guideline development groups as indicating efficacy. However, others argue that a composite of proximal vein thrombosis with clinical thromboembolism or even symptomatic pulmonary embolism alone should be the main measure. This debate is unfinished.⁸

Bleeding was reported as 'major' or 'clinically relevant but non-major'. The studies also reported bleeding from the wound, but this was not always considered as major bleeding if re-operation was not needed.

Assessment of efficacy

• total venous thromboembolism – a composite of subclinical deep vein thrombosis detected at routine venography (the most frequent component) and confirmed clinical deep vein thrombosis, non-fatal pulmonary embolism, fatal pulmonary embolism or death from any cause (which are much less common)
• major venous thromboembolism – subclinical proximal deep vein thrombosis, symptomatic venous thromboembolism, and death related to venous thromboembolism or all-cause mortality
• clinical venous thromboembolism – non-fatal or fatal

This orally active factor Xa inhibitor was compared with enoxaparin in four double-blind randomised trials for the prevention of venous thromboembolism. These were RECORD1 and RECORD2 for total hip replacement,^9,10and RECORD3 and RECORD4 for total knee replacement^11,12(Table 1). The rivaroxaban dose was 10 mg once daily starting 6–8 hours after wound closure. The enoxaparin dose was 40 mg once daily in RECORD 1, 2 and 3 (the studies most relevant to Australian practice) and 30 mg 12-hourly in RECORD4. Study drugs were given for about five weeks after hip replacement in RECORD1 and for about two weeks after knee replacement in RECORD3 and RECORD4. RECORD2 compared five weeks of rivaroxaban with 10–14 days of enoxaparin after hip replacement.

Efficacy (Table 1)

Rivaroxaban was more effective than enoxaparin in RECORD 1, 3 and 4, when used for a similar duration. For total thromboembolism there was a statistically significant relative risk reduction of 30–70%. For major thromboembolism the risk reduction was 40–90% which was statistically significant in RECORD1 and RECORD3. Clinical venous thromboembolism during two weeks after knee replacement was reduced in RECORD3 from 2.0 to 0.7% (relative risk reduction 65%, p = 0.005).

RECORD2, where rivaroxaban was continued for three weeks longer than enoxaparin, was primarily a comparison of treatment durations rather than an equal comparison of competing anticoagulants. It confirmed the value of post-discharge prophylaxis after hip replacement. Continuing rivaroxaban prophylaxis reduced cases of clinical venous thromboembolism within six weeks of surgery from 1.2% to 0.2% (p = 0.004) when compared with 10–14 days of enoxaparin.¹⁰

Pooled analysis of the results of the comparisons with 40 mg once-daily enoxaparin (RECORD 1, 2 and 3) found that after two weeks symptomatic venous thromboembolism and all-cause mortality was reduced from 0.8% to 0.4% by rivaroxaban (p = 0.005).¹³

Bleeding (Table 1)

The rates of major or clinically relevant non-major bleeding were similar with rivaroxaban and enoxaparin 40 mg once daily. The apparent increases in bleeding were small and statistically insignificant. An overview found that rates of wound infection and re-operation due to bleeding were low and comparable.¹³The near absence of 'major' bleeding is explained in part by a study definition which excluded wound-related bleeding unless it was fatal or led to re-operation.

This orally active thrombin inhibitor has been compared with enoxaparin in three double-blind randomised trials (Table 2). One trial was in hip replacement (RE-NOVATE)¹⁴and two were in knee replacement (RE-MODEL and RE-MOBILIZE).^15,16All compared two doses of dabigatran (220 mg once daily and 150 mg once daily) with enoxaparin. Treatment continued for 28–35 days in RE-NOVATE, 6–10 days in RE-MODEL, and 12–15 days in RE-MOBILIZE.

The studies most relevant to Australia are RE-NOVATE and RE-MODEL as dabigatran was given as a half-dose 1–4 hours after surgery, and 40 mg once-daily enoxaparin was started on the evening before surgery. In RE-MOBILIZE the initial half-dose of dabigatran was given 6–12 hours after surgery and 30 mg enoxaparin 12-hourly was started 12–24 hours after surgery.

Efficacy (Table 2)

Both doses of dabigatran were statistically 'non-inferior' to enoxaparin in RE-NOVATE and RE-MODEL. In RE-MOBILIZE the total rates of venous thromboembolism with the two dabigatran regimens were significantly higher than with twice-daily enoxaparin.

Bleeding (Table 2)

The rates of major or clinically relevant non-major bleeding were similar with the two dabigatran regimens and with enoxaparin. An overview showed a slight excess of bleeding with dabigatran 220 mg once daily, compared with enoxaparin 40 mg once daily, but this was not statistically significant.¹⁷

Rivaroxaban and dabigatran etexilate have no antidote. Circulating half-lives of 9–13 hours (rivaroxaban) and 12–14 hours (dabigatran) mean the first response to bleeding should be local and supportive since the drugs will wash out quickly once treatment is withdrawn. Routine tests of coagulation are unhelpful. Recombinant factor VIIa to bypass factor Xa or thrombin inhibition may help to control massive bleeding, although clinical experience is lacking.

Ximelagatran, the first orally active thrombin inhibitor, caused severe liver toxicity so all new oral anticoagulants are being closely watched for this and other unexpected organ effects. So far, an excess of liver effects has not been reported with rivaroxaban or dabigatran etexilate. There has not been an excess of myocardial infarction after surgery, which was another concern with ximelagatran. Other adverse events were equally distributed between treatment groups.

Over two-thirds of patients in these studies had surgery under regional (spinal or epidural) anaesthesia with or without a general anaesthetic, but study protocols required epidural anaesthesia to cease before the first (postoperative) dose of oral anticoagulant.

There are well-known limitations to any use of results from separate clinical trial programs to estimate relative efficacy of different drugs. Nevertheless, for rivaroxaban and dabigatran, in these large studies the demographics of study populations appear similar, as were study inclusion and exclusion criteria, so results should be broadly comparable – provided comparisons are of relative and not absolute outcome rates.

With that proviso, the results with rivaroxaban appear more impressive, since 10 mg once daily started 6–8 hours after surgery was superior to enoxaparin 40 mg once daily for several outcomes with a similar risk of bleeding. The efficacy and bleeding risk of dabigatran etexilate 220 mg once daily was similar to enoxaparin 40 mg once daily. While dabigatran etexilate 150 mg once daily was formally 'non-inferior' to enoxaparin, the total rates of venous thromboembolism were consistently higher than with 220 mg once daily or with enoxaparin 40 mg once daily and bleeding rates were not reduced. However, the definitions used for 'major bleeding' differed and reported bleeding rates with enoxaparin were consistently higher in the dabigatran trials, as were the total rates of venous thromboembolism. Comparisons with enoxaparin 30 mg 12-hourly (a higher total daily dose) are less relevant to Australian clinical practice.

Ongoing or recently published studies include evaluating the new oral anticoagulants for acute and longer-term treatment of venous thrombosis and pulmonary embolism, and in acute coronary syndromes. Prevention of systemic embolism in atrial fibrillation is also being studied.¹⁸

Both drugs are acceptable alternatives to enoxaparin 40 mg once daily for the prevention of venous thromboembolism after elective hip or knee replacement. While rivaroxaban is more effective than enoxaparin, dabigatran etexilate is no less effective. Bleeding risks are small and appear to be similar to those with enoxaparin. Attempts to draw fine distinctions about the relative safety of the two drugs are prevented by systematic differences between the two sets of study results. An advantage of the new drugs is the lack of the need for routine monitoring. Oral daily dosing will appeal especially to patients who need 3–4 weeks of continued prophylaxis after discharge from hospital.